HMG-CoA reductase inhibitors and method

ABSTRACT

Compounds of the following structure are HMG CoA reductase inhibitors and thus are active in inhibiting cholesterol biosynthesis, modulating blood serum lipids such as lowering LDL cholesterol and/or increasing HDl cholesterol, and treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and atherosclerosis  
                 
 
     and pharmaceutically acceptable salts thereof, wherein X is O or S;  
                 
 
     n is 0 or 1;  
     R 1  and R 2  are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl; and  
     R 3  to R 9  are as defined herein.

[0001] This application claims priority from U.S. provisionalapplication No. 60/211,595, filed Jun. 15, 2000.

Field of the Invention

[0002] The present invention relates to compounds and pharmaceuticalcompositions useful as hypocholesterolemic and hypolipidemic agents.More particularly, this invention concerns (1) certain inhibitors of theenzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAreductase) that include a pyridine containing nucleus attached by meansof a linker to an HMG-binding domain sidechain, (2) pharmaceuticalcompositions containing such compounds and (3) a method of loweringblood serum cholesterol levels and modulating blood serum lipid levelsemploying such pharmaceutical compositions.

Background of the Invention

[0003] U.S. Pat. No. 5,686,433 to Robl discloses the structure

[0004] wherein:

[0005] Am is a binding domain sidechain;

[0006] X is a linker;

[0007] R¹ and R² are the same or different and are each independentlyselected from

[0008] (i) hydrogen,

[0009] (ii) alkyl,

[0010] (iii) aryl,

[0011] (iv) cycloalkyl,

[0012] (v) aralkyl,

[0013] (vi) aralkoxy,

[0014] (vii) alkenyl,

[0015] (viii) cycloalkenyl, and

[0016] (ix) heterocyclo (e.g., thienyl, benzodioxolyl);

[0017] R³ is selected from

[0018] (i) hydrogen,

[0019] (ii) lower alkyl,

[0020] (iii) aryl,

[0021] (iv) cycloalkyl,

[0022] (v) alkoxy,

[0023] (vi) aralkyl,

[0024] (vii) aralkoxy,

[0025] (viii) alkenyl,

[0026] (ix) cycloalkenyl,

[0027] (x) halo-substituted alkyl,

[0028] (xi) adamantyl, and

[0029] (xii) heterocyclo (e.g., thienyl, benzodioxolyl);

[0030] R⁴ is selected from

[0031] (i) hydrogen,

[0032] (ii) lower alkyl,

[0033] (iii) aryl,

[0034] (iv) cycloalkyl,

[0035] (v) alkoxy,

[0036] (vi) aralkyl,

[0037] (vii) aralkoxy,

[0038] (viii) alkenyl,

[0039] (ix) cycloalkenyl,

[0040] (x) adamantyl,

[0041] (xi) halogen,

[0042] (xii) halo-substituted alkyl (e.g., trifluoromethyl), and

[0043] (xiii) heterocyclo (e.g., thienyl, benzodioxolyl); or R³ and R⁴taken together can be

[0044] but when A_(m) is

[0045] or a δ lactone thereof, R³ and R⁴ cannot be (CH═CH)₂;

[0046] R⁶ is hydrogen or lower alkyl;

[0047] R⁸ is hydrogen, lower alkyl, alkali metal, or alkaline earthmetal;

[0048] n is 0 or 1;

[0049] p is 3, 4 or 5;

[0050] q is 0, 1, 2, or 3; and

[0051] r is 0, 1, 2, or 3.

[0052] In preferred embodiments (Am) is an HMG-binding domain sidechainhaving a dihydroxy or a phosphinic acid function.

[0053] The phosphinic (or phosphonic when X is CH₂—O—) acid HMG-bindingdomain sidechain (A₁) is

[0054] wherein R⁵ and R⁷ are independently selected from hydrogen, loweralkyl, alkali metal ion and alkaline earth metal ion; and R⁶ is hydrogenor lower alkyl

[0055] The dihydroxy acid binding domain sidechain (A₂ is

[0056] wherein R⁶ is hydrogen or lower alkyl, R⁸ is hydrogen or loweralkyl in free acid form or in the form of a physiologically acceptableand hydrolyzable ester or δ lactone thereof (i.e., when Am is

[0057] In addition, R⁸ can be alkali metal ion or alkaline earth metalion.

[0058] A suitable linker (X) is —(CH₂)_(a)—, —CH═CH—, —C≡C—, —CH₂O—,wherein O is linked to the phosphorous atom or the aromatic anchor whenAm is A₁, and wherein O is linked to the aromatic anchor when Am is A₂,and wherein “a” is 1, 2, or 3.

BRIEF DESCRIPTION OF THE INVENTION

[0059] In accordance with the present invention, there are providedcertain pyridine-containing compounds that are potent inhibitors ofcholesterol biosynthesis by virtue of their ability to inhibit theenzyme 3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).

[0060] In particular, in its broadest chemical compound aspect, thepresent invention provides compounds of the formula

[0061] wherein X is O, S or NR₇;

[0062] n is 0 or 1;

[0063] R₁ and R₂ are the same or different and are independentlyselected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl,heteroaryl or cycloheteroalkyl;

[0064] R₃ is H, or lower alkyl;

[0065] R₄ is H, halogen, CF₃, hydroxy, alkyl, alkoxy, alkanoylamino,aroylamino, or cyano;

[0066] R₇ is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl;

[0067] R₈ is H or lower alkyl;

[0068] R₉ and R₁₀ are the same or different and are independentlyselected from H or alkyl, or where at least one of R₉ and R₁₀ is alkyl,R₉ and R₁₀ may be taken together with the carbon or carbons to whichthey are attached to form a 3 to 7 membered carbocyclic ring, which mayinclude a spirocyclic ring;

[0069] and represents a single bond or a double bond (which may be cisor trans);

[0070] and including pharmaceutically acceptable salts thereof where R₃is H, esters thereof, prodrug esters thereof, and all stereoisomersthereof.

[0071] Preferably, the Z group will be in form of a free acid, aphysiologically acceptable and hydrolyzable ester or δ lactone thereof,or an alkali metal salt, alkaline earth metal salt or an amino acidsalt.

[0072] Preferred are compounds of formula I of the invention wherein

[0073] R₁ and R₂ are independently selected from alkyl, cycloalkyl andaryl;

[0074] R₄ is H, alkyl or halogen;

[0075] X is O; and

[0076] n is o.

[0077] More preferred are compounds of formula I of the inventionwherein R₁ is aryl (especially substituted aryl as defined hereinafter);

[0078] R₂ is alkyl or cycloalkyl;

[0079] R₄ is H;

[0080] R₉ and R₁₀ are H;

[0081] X is O;

[0082] n is O; and

[0083] is a double bond.

[0084] Still more preferred are compounds of formula I of the inventionwherein

[0085] R₁ is substituted aryl, preferably 4-fluorophenyl,4-fluoro-3-methylphenyl or 3,5-dimethylphenyl;

[0086] R₂ is alkyl or cycloalkyl, preferably isopropyl, t-butyl orcyclopropyl;

[0087] R₄ is H;

[0088] X is O;

[0089] n is o;

[0090] is a double bond, preferably “trans”; and

[0091] or an alkali or alkaline earth metal salt thereof or an aminoacid salt.

[0092] Most preferred compounds of formula I of the invention will havethe structure

[0093] or an alkali or alkaline earth metal (such as Na, K or Ca) saltthereof, or an amino acid salt (such as arginine), wherein R₅ and R₆ arethe same or different and independently selected from H, halogen and/oralkyl (preferably 4-fluoro, 4-fluoro-3-methyl or 3,5-dimethyl); and

[0094] R₂ is alkyl or cycloalkyl, preferably isopropyl, t-butyl orcyclopropyl.

[0095] In another aspect, the present invention provides pharmaceuticalcompositions, useful as hypolipidemic or hypocholesterolemic agents, orhypotriglyceridemic agents, or anti-Alzheimer's agents, oranti-osteoporosis agents as well as other uses as described herein,comprising a hypolipidemic or hypocholesterolemic or hypotriglyceridemicor anti-Alzheimer's disease or anti-osteoporosis amount, or othertherapeutically effective amount (depending upon use) of a compound offormula I in accordance with this invention, in combination with apharmaceutically acceptable carrier.

[0096] In another aspect, the present invention provides a method ofinhibiting cholesterol biosynthesis or lowering blood serum cholesterollevels and/or modulating blood serum cholesterol levels such as loweringLDL cholesterol and/or increasing HDL cholesterol, or treatingdyslipidemia, mixed dyslipidemia, hyperlipidemia, hypercholesterolemia,hypo α-lipoproteinemia, LDL Pattern B, LDL Pattern A,hyperlipoproteinemia or hypertriglyceridemia, and other aberrations ofapolipoprotein B metabolism, or reducing levels of Lp(a), or treating orpreventing other cholesterol-related diseases, or treating or preventingor reversing progression of atherosclerosis, or preventing or treatingAlzheimer's disease, or preventing or treating osteoporosis and/orosteopenia, or reducing inflammatory markers such as C-reactive protein,or preventing or treating low grade vascular inflammation, or preventingor treating stroke, or preventing or treating dementia, or preventingand treating coronary heart disease (including primary and secondaryprevention of myocardial infarction), or preventing or treating stableand unstable angina, or primary prevention of coronary events, orsecondary prevention of cardiovascular events, or preventing or treatingperipheral vascular disease, preventing or treating peripheral arterialdisease, or preventing or treating acute vascular syndromes, orpreventing or reducing the risk of undergoing myocardialrevascularization procedures, or preventing or treating microvasculardiseases such as nephropathy, neuropathy, retinopathy and nephroticsyndrome or preventing or treating hypertension in a patient in need ofsuch treatment by administering a pharmaceutical composition inaccordance with the present invention as defined above.

[0097] In addition, in accordance with the present invention, a methodis provided for preventing or treating diabetes, especially Type 2diabetes, and related diseases such as insulin resistance,hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids orglycerol, obesity, Syndrome X, diabetic complications, dysmetabolicsyndrome, and related diseases, and sexual dysfunction, wherein atherapeutically effective amount of a compound of structure I isadministered to a patient in need of treatment.

[0098] In addition, in accordance with the present invention, a methodis provided for preventing and treating malignant lesions (such asductal carcinoma in situ of the breast and lobular carcinoma in situ ofthe breast), premalignant lesions (such as fibroadenoma of the breastand prostatic intraepithelial neoplasia (PIN), gastrointestinalmalignencies, liposarcomas and various other epithelial tumors(including breast, prostate, colon, ovarian, gastric and lung),cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn'sdisease, gastric ulceritis, and gallstones, and HIV infection, otherinfectious diseases, drug-induced lipodystrophy, and proliferativediseases such as psoriasis, wherein a therapeutically effective amountof a compound of structure I is administered to a human patient in needof treatment.

[0099] In addition, in accordance with the present invention, a methodis provided for improving coagulation homeostasis including reducingPAI-1 activity, reducing fibrinogen, and/or reducing plateletaggregation, and/or improving endothelial function, wherein atherapeutically effective amount of a compound of structure I isadministered to a patient in need of treatment.

[0100] In addition, in accordance with the present invention, a methodis provided for treating cholesterol related diseases, diabetes andrelated diseases, cardiovascular diseases, cerebrovascular diseases asdefined above and hereinafter and other diseases as set out above,wherein a therapeutically effective amount of a combination of acompound of structure I and a hypolipidemic agent, and/or lipidmodulating agent and/or antidiabetic agent and/or cardiovascular agent,cerebrovascular agent, and/or other type of therapeutic agent, isadministered to a patient in need of treatment.

[0101] In the above methods of the invention wherein a combination isadministered, the compound of structure I will be employed in a weightratio to the other therapeutic agent (depending upon its mode ofoperation) within the range from about 0.01:1 to about 500:1, preferablyfrom about 0.5:1 to about 100:1.

DETAILED DESCRIPTION OF THE INVENTION

[0102] In accordance with the present invention, there is providedcompounds useful in inhibiting the enzyme HMG-CoA reductase, whichinhibitors are useful as hypocholesterolemic agents, dyslipidemicagents, hypolipidemic agents, hypotriglyceridemic agents,anti-Alzheimer's disease agents, and antiosteoporosis agents as well asother uses as described herein.

[0103] The term “coronary events” as employed herein refers tomyocardial infarction, myocardial revascularization procedures, angina,cardiovascular death and acute coronary syndrome.

[0104] The term “cardiovascular diseases or events” as employed hereinrefers to atherosclerosis of the coronary arteries, myocardialinfarction, including primary MI and secondary MI, recurrent myocardialinfarction, angina pectoris (including stable and unstable angina),congestive heart failure, and sudden cardiac death.

[0105] The term “cerebrovascular diseases or events” as employed hereinrefers to cerebral infarction or stroke (caused by vessel blockage orhemmorage), or transient ischemia attack (TIA), syncope, atherosclerosisof the intracranial and/or extracranial arteries, and the like.

[0106] The term “cholesterol-related diseases” as employed herein refersto diseases involving elevated levels of LDL cholesterol, diseasesinvolving regulation of LDL receptors, diseases involving reduced levelsof HDL cholesterol, dyslipidemia, hyperlipidemia, elevated LDL PatternB, elevated LDL Pattern A, hypercholesterolemia, hypo α-lipoproteinemia(low HDL cholesterol syndrome), hyperlipoproteinemia, elevated Lp(a)levels, hypertriglyceridemia, other aberrations of apolipoprotein Bmetabolism, heterozygous familial, presumed familial combined andnon-familial (non-FH) forms of primary hypercholesterolemia (includingFrederickson Types IIa and IIb), cholesterol ester storage disease, andcholesterol ester transfer protein disease, and related diseases.

[0107] The conditions, diseases, and maladies collectively referenced toas “Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson, J.Clin. Endocrinol. Metab., 1997, 82, 727-734, and other publications)include hyperglycemia and/or prediabetic insulin resistance syndrome,and is characterized by an initial insulin resistant state generatinghyperinsulinemia, dyslipidemia, and impaired glucose tolerance, whichcan progress to Type II diabetes, characterized by hyperglycemia, whichcan progress to diabetic complications.

[0108] The term “diabetes and related diseases” refers to Type IIdiabetes, Type I diabetes, impaired glucose tolerance, obesity,hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complicationsand hyperinsulinemia.

[0109] The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

[0110] The term “other type(s) of therapeutic agents” as employed hereinrefers to one or more antidiabetic agents (other than compounds offormula I), one or more anti-obesity agents, and/or one or morelipid-lowering agents, one or more lipid modulating agents (includinganti-atherosclerosis agents), other types of anti-atherosclerosisagents, and/or one or more antiplatelet agents, one or more agents fortreating hypertension, one or more anti-cancer drugs, one or more agentsfor treating arthritis, one or more anti-osteoporosis agents, one ormore anti-obesity agents, one or more agents for treatingimmunomodulatory diseases, and/or one or more agents for treatinganorexia nervosa.

[0111] The term “lipid-modulating” agent as employed herein refers toagents which lower LDL and/or raise HDL and/or lower triglyceridesand/or lower total cholesterol and/or other known mechanisms fortherapeutically treating lipid disorders.

[0112] The term “other types of anti-atherosclerosis agents” as employedherein refers to conventional anti-atherosclerosis agents includinglipoxygenase inhibitors, ACAT inhibitors, antioxidants, PPAR δ agonists,phospholipase inhibitors including PLA-2 inhibitors and/or other knownanti-atherosclerotic agents.

[0113] The terms pharmaceutically acceptable “salt” and “salts” refer tobasic salts formed with inorganic and organic bases. Such salts includeammonium salts; alkali metal salts, such as lithium, sodium andpotassium salts (which are preferred); alkaline earth metal salts, suchas calcium and magnesium salts; salts with organic bases, such as aminelike salts (e.g., dicyclohexylamine salt, benzathine,N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acidslike arginine, lysine and the like; and zwitterions, the so-called“inner salts”. Nontoxic, pharmaceutically acceptable salts arepreferred, although other salts are also useful, e.g., in isolating orpurifying the product.

[0114] The term pharmaceutically acceptable “salt” and “salts” alsoincludes acid addition salts. These are formed, for example, with stronginorganic acids, such as mineral acids, for example sulfuric acid,phosphoric acid or a hydrohalic acid such as HCl or HBr, with strongorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids,for example ascorbic, glycolic, lactic, malic, tartaric or citric acid,such as amino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C1-C4) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid.

[0115] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, cycloheteroalkyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio.

[0116] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbonsforming the ring, preferably 3 to 10 carbons, forming the ring and whichmay be fused to 1 or 2 aromatic rings as described for aryl, whichincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

[0117] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, heteroaryl, cycloheteroalkyl, amino, alkylamino,nitro, cyano, thiol and/or alkylthio and/or any of the substituents foralkyl.

[0118] The term “cycloalkenyl” as employed herein alone or as part ofanother group refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

[0119] The term “alkanoyl” as used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

[0120] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons, and more preferably 1 to 8 carbons in the normal chain, whichinclude one to six double bonds in the normal chain, such as vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike, and which may be optionally substituted with 1 to 4 substituents,namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol,alkylthio and/or any of the alkyl substituents set out herein.

[0121] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons and more preferably 2 to 8 carbons in the normal chain, whichinclude one triple bond in the normal chain, such as 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any ofthe alkyl substituents set out herein.

[0122] The terms “arylalkenyl” and “arylalkynyl” as used alone or aspart of another group refer to alkenyl and alkynyl groups as describedabove having an aryl substituent.

[0123] Where alkyl groups as defined above have single bonds forattachment to other groups at two different carbon atoms, they aretermed “alkylene” groups and may optionally be substituted with 1 or 2substituents as defined above for “alkyl”, such as, for example, alkyl,halo, hydroxy, alkoxy and/or cycloalkyl.

[0124] Where alkenyl groups as defined above and alkynyl groups asdefined above, respectively, have single bonds for attachment at twodifferent carbon atoms, they are termed “alkenylene groups” and“alkynylene groups”, respectively, and may optionally be substitutedwith 1 or 2 substituents as defined above for “alkenyl” and “alkynyl”.

[0125] The term “halogen” or “halo” as used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine as wellas CF₃, with chlorine or fluorine being preferred.

[0126] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0127] Unless otherwise indicated, the term “aryl” as employed hereinalone or as part of another group refers to monocyclic and bicyclicaromatic groups containing 6 to 10 carbons in the ring portion (such asphenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one to three additional rings fused to a carbocyclicring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings for example

[0128] and may be optional substitued through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, halophenyl, benzoyloxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, alkanoyl, aryl or any of the other arylcompounds mentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the alkyl substituents set outherein.

[0129] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

[0130] Unless otherwise indicated, the term “substituted amino” asemployed herein alone or as part of another group refers to aminosubstituted with one or two substituents, which may be the same ordifferent, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

[0131] Unless otherwise indicated, the term “lower alkylthio”,“alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or aspart of another group includes any of the above alkyl, aralkyl or arylgroups linked to a sulfur atom.

[0132] Unless otherwise indicated, the term “lower alkylamino”,“alkylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl groups linked to a nitrogen atom.

[0133] Unless otherwise indicated, the term “acyl” as employed herein byitself or part of another group, as defined herein, refers to an organicradical linked to a

[0134] carbonyl group; examples of acyl groups include any of the R¹groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl,aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and thelike.

[0135] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 to 2hetero atoms such as nitrogen, oxygen and/or sulfur, linked through acarbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(r) (where r is 1, 2 or 3), such as

[0136] and the like. The above groups may include 1 to 4 substituentssuch as alkyl, halo, oxo and/or any of of the alkyl substituents set outherein. In addition, any of the cycloheteroalkyl rings can be fused to acycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0137] Unless otherwise indicated, the term “heteroaryl” as used hereinalone or as part of another group refers to a 5- or 6-membered aromaticring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygenor sulfur,and such rings fused to an aryl, cycloalkyl, heteroaryl orcycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includespossible N-oxides. The heteroaryl group may optionally include 1 to 4substituents such as any of the substituents set out above for alkyl.Examples of heteroaryl groups include the following:

[0138] and the like.

[0139] The term “cycloheteroalkylalkyl” as used herein alone or as partof another group refers to cycloheteroalkyl groups as defined abovelinked through a C atom or heteroatom to a (CH₂)_(r) chain.

[0140] The term “heteroarylalkyl” or “heteroarylalkenyl” as used hereinalone or as part of another group refers to a heteroaryl group asdefined above linked through a C atom or heteroatom to a —(CH₂)_(r)—chain, alkylene or alkenylene as defined above.

[0141] The term “polyhaloalkyl” as used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

[0142] The term “polyhaloalkoxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃ O or CF₃CF₂CH₂O.

[0143] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

[0144] The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like. Inaddition, prodrug esters which are known in the art for carboxylic andphosphorus acid esters such as methyl, ethyl, benzyl and the like.

[0145] Examples of such prodrug esters include

[0146] Other examples of suitable prodrug esters include

[0147] wherein R^(a) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl,halogen or alkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is0, 1 or 2.

[0148] Where the compounds of structure I are in acid form they may forma pharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, lysine (D or L), ethylenediamine,t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS),N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

[0149] Compounds of the invention may be prepared by the followingmethod.

[0150] Referring to Reaction Scheme 1, Knovenagel condensation ofreadily available beta-keto ester 1, where R is lower alkyl, withaldehyde 2 under standard conditions (e.g. HOAc, piperidine, toluene,reflux) affords the corresponding adduct 3. Base induced 1,4-addition ofketone 4 (e.g. LiN(TMS)₂ in THF or EtONa in EtOH) provides the adduct 5,usually as a mixture of diastereomers.

[0151] Conversion of the 1,5-diketone 5 to the pyridyl ester 6 may beeffected by treatment with an ammonia source (such as NH₄OAc) in thepresence of an oxidant (such as Cu(OAc)2 or oxygen) in a suitablesolvent (such as refluxing HOAc), or by reaction of 5 with hydroxylaminehydrochloride in HOAc with heat. The ester functionality of 6 can bereduced by standard methods (LiAlH₄, DIBAL, LIBH₄) to give alcohol 7which can subsequently be converted to the corresponding halide 8 (e.g.PBr₃ in CH₂Cl₂, CBr₄/PPh₃ in CH₃CN or POCl₃). Conversion of halide 8 tothe phosphorus compound 9 where W is Ph or alkyl is effected bytreatment of 8 with W₂POEt in toluene. Conversion of halide 8 tocompound 9 where W is OR (R is lower alkyl) may be effected by thereaction of 8 with HOP(OR)2/base/THF or by Arbuzov reaction with P(OR)₃.Witting reaction between 9 and aldehyde 10 (aldehyde 10 has beenpreviously described in U.S. Pat. No. 5,686,433) may be effected understandard conditions with base (n-BuLi, LiN(TMS)₂, LDA) in an appropriatesolvent (THF, Et₂O, toluene, DMPU) to afford the adduct 11. Treatment of11 under acidic conditions (e.g. TFA, HCl) effects the conversion of 11to lactone Ia. Saponification of Ia to Ib (where R₃ is alkali metal, oralkaline earth metal) can be effected by treatment of Ia with aqueousbase or subsequently acidified to give Ib where R₃ is H. Additionally,Ia can be treated with an alcohol of the type R₃OH under basicconditions to form the corresponding esters of Ib.

[0152] As seen in Reaction Scheme 2, the saturated derivatives ofcompound I (where is CH₂—CH₂) are obtained by catalytic (Pd/C, Pt/C,Pd(OH)₂) hydrogenation of 11, Ia, or Ib to afford 12, Ic, or Id,respectively. Compound 12 may be converted to Ic and Id following theearlier described methods for the conversion of compound 11 to Ia andIb.

[0153] The synthesis of compounds I wherein is CH═CH and n is 1, isdescribed in Scheme 3. Bis-silylation of compound Ib¹ with a bulkysilyichioride (e.g., ClSi(t-butyl)Ph₂, ClSi(t-butyl)Me₂, ClSiPh₃) in thepresence of a suitable base (e.g., TEA, imidazole, pyridine) and solvent(e.g., CH₂Cl₂, THF) provides compound Ib². Treatment of Ib² withoxidants such as m-CPBA or CF₃CO₃H in an appropriate solvent such asCH₂Cl₂ or HOAc affords N-oxide Ib ³. Desilylation of Ib³ (TBAF/HOAc/THFor HF/CH₃CN) gives Ib ⁴which may be saponified to Ib⁵ using aqueoussolutions of a metal hydroxide in an appropriate solvent (e.g., MeOH,dioxane).

[0154] Additionally, compound Id¹ may be oxidized and saponified, asdescribed above, to provide compounds I wherein is CH₂CH₂ and n is 1(e.g., compounds Id² and ID³) as shown in Scheme 4.

[0155] It will be appreciated that in Schemes 1 to 4, with respect tocompounds 4, 5, 6, 7, 8, 9, 11, Ia, Ib, 12, Ic, Id, Ib¹, Ib², Ib³, Ib⁴,Ib⁵, Id¹, Id² and Id³, although substituents R₉ and R₁₀ as definedhereinbefore are not included in these compounds, Schemes 1 to 4 may becarried out where such compounds include R₉ and R₁₀ substituents.

[0156] Scheme 5 depicts a preferred method for preparing the HMG CoAreductase inhibitor of formula I of the invention using theJulia-Kocienski olefination reaction employing 4-pyridylcarboxylaldehyde (18) and chiral sulfone (16). The desired transintermediate (19) is isolated in high yield and optical purity which isconverted to the final product of the invention. As will be seen, thechiral sulfone (16), a key intermediate in the Julia-Kocienski step, isprepared in three steps starting from the commercially available Kanekaalcohol (12) via triflate (13) and sulfide intermediate (15).

[0157] Referring to Scheme 5, treatment of commercially available chiralalcohol (12) with triflic anhydride and triethylamine in dichloromethaneat low temperature (for example 0 to −30° C.) affords triflate (13).Other pyridine or amine bases may be employed. Triflate (13) (withoutbeing isolated) is carried onto the next step without furtherpurification. A methylene chloride solution of triflate (13)is treatedwith 1-phenyl-1H-tetrazole-5-thiol (14) to provide the chiral sulfide(15) which is oxidized with hydrogen peroxide in the presence ofcatalytic ammonium heptamolybdate tetrahydrate to give crystallinesulfone (16). Other oxidant, such as m-chloro-p-benzoic acid (mCPBA) meybe employed.

[0158] Addition of LiHMDS or NaHMDS to a mixture of sulfone (16) andpyridine carboxylaldehyde (18) in THF at low temperature (−78 to −35°C.) provides trans olefin (19) in high diastereoselectivity (>99%).

[0159] The pyridine aldehyde (18) is obtained as a crystalline solidform the corresponding ester (17). Reduction of ester (17) with Red-Alfollowed by oxidation with Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy)gives aldehyde (18) in high yield. The final compound Ie of theinvention is prepared in a one pot procedure starting from (19) withoutisolating any intermediates. Removal of acetonide under acidic conditionprovides diol Ie of the invention which upon further treatment withsodium hydroxide gives the sodium salt of the acid If of the invention.Subsequent treatment of If with acid followed by the addition ofarginine produces crystalline arginine salt of the invention Ig.

[0160] In addition, in accordance with the present invention,intermediates 6, 7, 8, 9, 11 and 12 are novel compounds and form part ofthe present invention. These compounds have the general structure

[0161] wherein X is O, S or NR₇, R₁, R₂, R₄, R₇, R₉ and R₁₀ as are asdefined above, Q is

[0162] Thus, the intermediates of the invention can have the followingstructures:

[0163] Compounds 6, 7, 8, 9, 11 and/or 12 may include R₉ and R₁₀substituents.

[0164] Compounds containing dihydroxy acid HMG-CoA binding domain sidechains may be prepared in homochiral form, which is preferred, or m aybe prepared as racemic mixtures (3S★, 5R★) and may later be resolved toobtain the 3S, 5R isomer. Thus, the intermediates of the invention canhave the following structures:

[0165] Compounds containing dihydroxy acid HMG-CoA binding domain sidechains may be prepared in homochiral form, which is preferred, or may beprepared as racemic mixtures (3S★, 5R★) and may later be resolved toobtain the 3S, 5R isomer.

[0166] The compounds of the invention are inhibitors of3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus areuseful in inhibiting cholesterol biosynthesis and/or in loweringtriglycerides, in a manner similar to atorvastatin, pravastatin,simvastatin, lovastatin, cerivastatin, visastatin (or rosuvastatin)(Astra Zeneca ZD4522), fluvastatin, itavastatin (or pitavastatin) andthe like.

[0167] A further aspect of the present invention is a pharmaceuticalcomposition containing at least one of the compounds of formula I of thepresent invention in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles of diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration.The compounds can be administered by an oral route, for example, in theform of tablets, capsules, granules or powders, or they can beadministered by a parenteral route in the form of injectablepreparations. Such dosage forms contain from 0.1 to 1500 mg of activecompound per dosage, for use in the treatment. The dose to beadministered depends on the unitary dose, the symptoms, and the age andthe body weight of the patient.

[0168] The compounds of the present invention can be administered in asimilar manner as known compounds suggested for use in inhibitingcholesterol biosynthesis, such as pravastatin, lovastatin, simvastatin,visastatin (or rosuvastatin), atorvastatin, cerivastatin, fluvastatin,itavastatin (or pitavastatin), and the like, in mammalian species suchas humans, dogs, cats and the like. Thus, the compounds of the inventionmay be administered in an amount from about 0.1 to 500 mg in a singledose or in the form of individual doses from 1 to 4 times per day,preferably 0.2 to 100 mg daily or in sustained release form.

[0169] The HMG CoA reductase inhibitors of formula I may be employed incombination with all therapeutic agents which are useful in combinationwith HMG CoA reductase inhibitors.

[0170] Thus, where desired, the compounds of structure I may be used incombination with one or more hypolipidemic agents or lipid-loweringagents, or lipid agents, or lipid modulating agents, and/or one or moreother types of therapeutic agents including antidiabetic agents,anti-obesity agents, antihypertensive agents, platelet aggregationinhibitors, anti-Alzheimer's agents, anti-dementia agents,anti-osteoporosis agents, and/or hormone replacement therapeutic agents,and/or other therapeutic agents, and/or other cardiovascular agents(including anti-anginal agents, anti-arrhythmic agents,anti-atherosclerosis agents, anti-inflammatory agents, anti-plateletagents, anti-heart failure agents), anti-cancer agents, anti-infectiveagents, hormone replacement agents, growth hormone secretagogues,selective androgen receptor modulators, and/or other therapeutic agentswhich may be administered orally in the same dosage form or in aseparate oral dosage form, or by injection.

[0171] The hypolipidemic agent or lipid-lowering agent or other lipidagent or lipid modulating agent which may be optionally employed incombination with the compounds of formula I of the invention may include1, 2, 3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalenesynthetase inhibitors, PPAR α agonists, PPAR dual α/γ agonists, PPAR δagonists, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity,cholesteryl ester transfer protein inhibitors, bile acid sequestrants,and/or nicotinic acid and derivatives thereof.

[0172] MTP inhibitors employed herein include MTP inhibitors disclosedin U.S. Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875,5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

[0173] All of the above U.S. Pat. and applications are incorporatedherein by reference.

[0174] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0175] The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0176] The hypolipidemic agent may be an HMG CoA reductase inhibitorwhich includes, but is not limited to, mevastatin and related compoundsas disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) andrelated compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatinand related compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin(Nissan/Sankyo's nisvastatin (NK-104) or itavastatin), disclosed in U.S.Pat. No. 5,011,930, Shionogi-Astra/Zeneca rosuvastatin (visastatin(ZD-4522)) disclosed in U.S. Pat. No. 5,260,440, and related statincompounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs ofmevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Pat. No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Pat. Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Pat. Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. No. 5,506,219 and 5,691,322.

[0177] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0178] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, a-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. No.4,871,721 and 4,924,024 and in Biller, S.A., Neuenschwander, K.,Ponpipom, M.M., and Poulter, C.D., Current Pharmaceutical Design, 2,1-40 (1996).

[0179] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R.W. et al, J. A. C. S.,1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhDdissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary.

[0180] Other hypolipidemic agents suitable for use herein include, butare not limited to, fibric acid derivatives, such as fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®) and cholestagel (Sankyo/Geltex), as well aslipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolaminederivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid (niacin), acipimox,acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0181] The other hypolipidemic agent may be an ACAT inhibitor (whichalso has anti-atherosclerosis activity) such as disclosed in, Drugs ofthe Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-loll iseffective in the prevention and regression of aortic fatty streak areain hamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl] ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd), as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

[0182] The hypolipidemic agent may be an upregulator of LDL receptoractivity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0183] The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

[0184] The other lipid agent or lipid-modulating agent may be acholesteryl transfer protein inhibitor (CETP) such as Pfizer'sCP-529,414 as well as those disclosed in WO/0038722 and in EP 818448(Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795 as well asCETi-1 and JTT-705.

[0185] The hypolipidemic agent may be an ileal Na⁺/bile acidcotransporter inhibitor such as disclosed in Drugs of the Future, 24,425-430 (1999).

[0186] The ATP citrate lyase inhibitor which may be employed in thecombination of the invention may include, for example, those disclosedin U.S. Pat. No. 5,447,954.

[0187] The other lipid agent also includes a phytoestrogen compound suchas disclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201;

[0188] a beta-lactam cholesterol absorption inhibitor such as disclosedin EP 675714;

[0189] an HDL upregulator such as an LXR agonist, a PPAR α-agonistand/or an FXR agonist;

[0190] an α-glucosidase inhibitor, an aldose reductase inhibitor and/oran LDL catabolism promoter such as disclosed in EP 1022272;

[0191] a sodium-proton exchange inhibitor such as disclosed in DE19622222;

[0192] an LDL-receptor inducer or a steroidal glycoside such asdisclosed in U.S. Pat. No. 5,698,527 and GB 2304106;

[0193] an anti-oxidant such as beta-carotene, ascorbic acid,α-tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin Cand an antihomocysteine agent such as folic acid, a folate, Vitamin B6,Vitamin B12 and Vitamin E;

[0194] isoniazid as disclosed in WO 97/35576;

[0195] a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701;

[0196] a PPAR δagonist for treating dyslipidemia;

[0197] or a sterol regulating element binding protein-I (SREBP-1) asdisclosed in WO 2000/050574, for example, a sphingolipid, such asceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof.

[0198] Preferred hypolipidemic agents are pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, pitavastatin androsuvastatin, as well as niacin and/or cholestagel.

[0199] The above-mentioned U.S. patents are incorporated herein byreference. The amounts and dosages employed will be as indicated in thePhysician's Desk Reference and/or in the patents set out above or asotherwise known in the art.

[0200] The compounds of formula I of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

[0201] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0202] The dosages and formulations for the hypolipidemic agent or otherlipid agent or lipid modulating agent will be as disclosed in thevarious patents and applications discussed above.

[0203] The dosages and formulations for the other hypolipidemic agent orother lipid agent or lipid modulating agent to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference.

[0204] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100mg, one to four times daily.

[0205] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0206] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0207] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0208] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 0.5 to about 80 mg, and morepreferably from about 1 to about 40 mg.

[0209] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0210] The anti-atherosclerotic agent includes a lipoxygenase inhibitorincluding a 15-lipoxygenase (15-LO) inhibitor such as benzimidazolederivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosedin WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LOinhibitors as disclosed by Sendobry et al “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties,” Brit. J.Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0211] The compounds of formula I and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0212] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0213] The antidiabetic agent which may be optionally employed incombination with the HMG-CoA reductase inhibitor of formula I may be 1,2, 3 or more antidiabetic agents or antihyperglycemic agents includinginsulin secretagogues or insulin sensitizers, which may includebiguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductaseinhibitors, PPAR γ agonists such as thiazolidinediones, PPAR α agonists(such as fibric acid derivatives), PPAR δ antagonists or agonists, aP2inhibitors, PPAR α/γ dual agonists, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/ormeglitinides, as well as insulin, and/or glucagon-like peptide-1(GLP-1), and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1Binhibitor).

[0214] The antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

[0215] Where the antidiabetic agent is a biguanide, the compounds ofstructure I will be employed in a weight ratio to biguanide within therange from about 0.001:1 to about 10:1, preferably from about 0.01:1 toabout 5:1.

[0216] The antidiabetic agent may also preferably be a sulfonyl ureasuch as glyburide (also known as glibenclamide), glimepiride (disclosedin U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide,other known sulfonylureas or other antihyperglycemic agents which act onthe ATP-dependent channel of the β-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms.

[0217] The compounds of structure I will be employed in a weight ratioto the sulfonyl urea in the range from about 0.01:1 to about 100:1,preferably from about 0.02:1 to about 5:1.

[0218] The oral antidiabetic agent may also be a glucosidase inhibitorsuch as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol(disclosed in U.S. Pat. No. 4,639,436), which may be administered in thesame or in a separate oral dosage forms.

[0219] The compounds of structure I will be employed in a weight ratioto the glucosidase inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05:1 to about 10:1.

[0220] The compounds of structure I may be employed in combination witha PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®,disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

[0221] The compounds of structure I will be employed in a weight ratioto the thiazolidinedione in an amount within the range from about 0.01:1to about 100:1, preferably from about 0.05:1 to about 10:1.

[0222] The sulfonyl urea and PPAR γ agonists in amounts of less thanabout 150 mg oral antidiabetic agent may be incorporated in a singletablet with the compounds of structure I.

[0223] The compounds of structure I may also be employed in combinationwith a antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) or mimetic such as GLP-1(1-36) amide, GLP-1(7-36)amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener,the disclosure of which is incorporated herein by reference), as well asAC2993 (Amylen) and LY-315902 (Lilly), which may be administered viainjection, intranasal, inhalation or by transdermal or buccal devices.

[0224] Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

[0225] Where present, metformin or salt thereof may be employed inamounts within the range from about 500 to about 2000 mg per day whichmay be administered in single or divided doses one to four times daily.

[0226] Where present, the PPAR anti-diabetic agent may be employed inamounts within the range from about 0.01 to about 2000 mg/day which maybe administered in single or divided doses one to four times per day.

[0227] Where present insulin and other anti-diabetic agents as set outabove may be employed in formulations, amounts and dosing as indicatedby the Physician's Desk Reference.

[0228] Where present GLP-1 peptides or mimetics may be administered inoral buccal formulations, by nasal administration or parenterally asdescribed in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and5,631,224 which are incorporated herein by reference.

[0229] The antidiabetic agent or other lipid agent may also be a PPARmodulator such as a PPAR α/γ dual agonist such as AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) aswell as those disclosed by Murakami et al, “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998), and in U.S. application Ser. No. 09/664,598, filed Sep. 18,2000, (attorney file LA29) the disclosure of which is incorporatedherein by reference, employing dosages as set out therein, whichcompounds designated as preferred are preferred for use herein.

[0230] The antidiabetic agent may be an SGLT2 inhibitor such asdisclosed in U.S. application Ser. No. 09/679,027, filed Oct. 4, 2000(attorney file LA49), employing dosages as set out therein. Preferredare the compounds designated as preferred in the above application.

[0231] The antidiabetic agent may be an aP2 inhibitor such as disclosedin U.S. application Ser. No. 09/391,053, filed Sept. 7, 1999, and inU.S. application Ser. No. 09/519,079, filed Mar. 6, 2000 (attorney fileLA27), employing dosages as set out herein. Preferred are the compoundsdesignated as preferred in the above application.

[0232] The antidiabetic agent may be a DP4 inhibitor such as disclosedin application Ser. No. 09/788,173, filed Feb. 16, 2001 (attorney fileLA50), W099/38501, W099/46272, W099/67279 (PROBIODRUG), W099/67278(PROBIODRUG), W099/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0233] The meglitinide which may optionally be employed in combinationwith the compound of formula I of the invention may be repaglinide orStarlix® (Novartis), nateglinide (Novartis) or KAD1229 (PF/Kissei), withrepaglinide being preferred.

[0234] The antidiabetic compound may be a melanocortin receptor agonistsuch as a spiropiperidine as disclosed in WO 99/64002.

[0235] The HMG CoA reductase inhibitor of formula I will be employed ina weight ratio to the meglitinide, PPAR modulator such as a PPAR γagonist, PPAR α agonist, PPAR δ agonits or antagonist, PPAR α/γ dualagonist, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor or otherantidiabetic agent within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

[0236] The other type of therapeutic agent which may be optionallyemployed with the HMG CoA reductase inhibitor of formula I may be 1, 2,3 or more of an anti-obesity agent including a beta 3 adrenergicagonist, a lipase inhibitor, a serotonin (and dopamine) reuptakeinhibitor, an aP2 inhibitor, a thyroid receptor beta drug, a PTP-1Binhibitor, an anorectic agent, a PPAR modulator including PPAR γantagonists, PPAR α agonists, PPAR δ antagonists, a CCKA agonist, aleptin inhibitor such as a leptin receptor activator, a neuropeptide γantagonist, a melanocortin-4-receptor (MC4R) agonist, a fatty acidoxidation upregulator or inducer (such as Famoxin® Genset).

[0237] The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

[0238] The neuropeptide γ antagonists which may be optionally employedin combination with a compound of formula I include those described inWO 0113917 (BMS) or in U.S. Pat. No. 6,218,408 (Synaptic) and in WO0114376 (Banyu).

[0239] The lipase inhibitor which may be optionally employed incombination with a compound of formula I may be orlistat or ATL-962(Alizyme), with orlistat being preferred.

[0240] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

[0241] The thyroid receptor beta compound which may be optionallyemployed in combination with a compound of formula I may be a thyroidreceptor ligand as disclosed in W097/21993 (U. Cal SF), W099/00353(KaroBio), GB98/284425 (KaroBio), and U.S. Provisional Application60/183,223 filed Feb. 17, 2000, with compounds of the KaroBioapplications and the above U.S. provisional application being preferred.

[0242] The anorectic agent which may be optionally employed incombination with a compound of formula I may be dexamphetamine,phentermine, phenylpropanolamine or mazindol, with dexamphetamine beingpreferred.

[0243] The CCKA agonists which may be employed herein includeGlaxo-SmithKline's GI-181,771 and Sanofi's SR146,131.

[0244] The PTP-1B inhibitor which may be an anti-oesity and/or anantidiabetic agent include those disclosed in WO 99/585,521, WO99/58518, Wo 99/58522 and WO 99/61435.

[0245] The anti-obesity agent employed may also be Pfizer's P57 orCP-644,673 (licensed from Phytopharm).

[0246] The various anti-obesity agents described above may be employedin the same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

[0247] The antihypertensive agents which may be employed in combinationwith the HMG CoA reductase inhibitors of the invention include ACEinhibitors, angiotensin II receptor antagonists,NEP inhibitors such ascandoxatril, NEP/ACE inhibitors, as well as calcium channel blockers(such as verapamil and amlodipine besylate), T-channel calciumantagonists (such as mibefradil), β-adrenergic blockers, diuretics,α-adrenergic blockers (such as doxazosin mesylate and terazosin HCl),dual action receptor antagonists (DARA), heart failure drugs such asdigoxin, and other types of antihypertensive agents.

[0248] The angiotensin converting enzyme inhibitor which may be employedherein includes those containing a mercapto (-S-) moiety such assubstituted proline derivatives, such as any of those disclosed in U.S.Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril,that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, beingpreferred, and mercaptoacyl derivatives of substituted prolines such asany of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril beingpreferred.

[0249] Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

[0250] Other examples of angiotensin converting enzyme inhibitors whichmay be employed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline or (ceronapril) being preferred, phosphinylalkanoyl prolinesdisclosed in U.S. Pat. No. 4,168,267 mentioned above with fosinoprilbeing preferred, any of the phosphinylalkanoyl substituted prolinesdisclosed in U.S. Pat. No. 4,337,201, and the phosphonamidates disclosedin U.S. Pat. No. 4,432,971 discussed above.

[0251] Other examples of ACE inhibitors that may be employed hereininclude Beecham's BRL 36,378 as disclosed in European Pat. ApplicationNos. 80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v andJap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(★)R(★)]]3R(★)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid HCl)disclosed inPharmacologist 26:243, 266 (1984), WY-44221 (Wyeth) disclosed in J. Med.Chem. 26:394 (1983).

[0252] Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

[0253] NEP/ACE inhibitors may also be employed herein in that theypossess neutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359, U.S. Pat. No. 5,525,723, European Patent Application0599,444, 0481,522, 0599,444, 0595,610, European Patent Application0534363A2, 534,396 and 534,492, and European Pat. Application 0629627A2.

[0254] Preferred are those NEP/ACE inhibitors and dosages thereof whichare designated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, gemopatrilat([S[(R★,R★)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid) and CGS 30440.

[0255] The angiotensin II receptor antagonist (also referred to hereinas angiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, tasosartan or eprosartan, with irbesartan, losartan orvalsartan being preferred.

[0256] A preferred oral dosage form, such as tablets or capsules, willcontain the ACE inhibitor or AII antagonist in an amount within therange from abut 0.1 to about 500 mg, preferably from about 5 to about200 mg and more preferably from about 10 to about 150 mg.

[0257] For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

[0258] Where a drug is to be administered intravenously, it will beformulated in conventional vehicles, such as distilled water, saline,Ringer's solution or other conventional carriers.

[0259] It will be appreciated that preferred dosages of ACE inhibitorand AII antagonist will be as set out in the latest edition of thePhysician's Desk Reference (PDR).

[0260] Dual action receptor antagonists (DARA) suitable for use hereininclude those disclosed in U.S. applications Ser. No. 09/513,779, filedFeb. 25, 2000, and Ser. No. 09/604,322, filed Jun. 26, 2000.

[0261] Other examples of preferred antihypertensive agents suitable foruse herein include omapatrilat (Vanlev®), gemopatrilat, amlodipinebesylate (Norvasc®), prazosin HCl (Minipress®), verapamil, nifedipine,diltiazem, felodipine, nisoldipine, isradipine, nicardipine, betablockers such as nadolol, atenolol (Tenormin®) , sotalol, terazosin,doxazosin, carvedilol, and propranolol, and clonidine HCl (Catapres®).

[0262] Diuretics which may be employed in combination with compounds offormula I include hydrochlorothiazide, torasemide, furosemide,spironolactone, and indapamide.

[0263] Antiplatelet agents which may be employed in combination withcompounds of formula I of the invention include aspirin, clopidogrel,ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide,anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.

[0264] The antihypertensive agents, diuretics and antiplatelet drugs maybe employed in amounts as indicated in the PDR. Ifetroban may beemployed in amounts as set out in U.S. Pat. No. 5,100,889.

[0265] Anti-Alzheimer's agents or anti-dementia agents suitable for useherein with the HMG CoA reductase inhibitors of the invention includetacrine HCl (Cognex®) and donepezil (Aricept®), as well as γ-secretaseinhibitors, β-secretase inhibitors and/or antihypertensive agents.Dosages employed will be as set out in the PDR.

[0266] Antiosteoporosis agents suitable for use herein in combinationwith the HMG CoA reductase inhibitors of the invention includeparathyroid hormone or bisphosphonates, such as MK-217 (alendronate)(Fosamax®) as well as Ca receptor agonists and progestin receptoragonists. Dosages employed will be as set out in the PDR.

[0267] The hormone replacement therapeutic agents, where present, willbe employed in dosages as set out in the latest edition of the PDR.Examples of such agents include selective estrogen receptor modulators(SERMs) such as raloxifen, tamoxifen or lasoxifen.

[0268] The HMG CoA reductase compound of the invention may also beemployed in combination with a tyrosine kinase inhibitor such asdisclosed in WO 2000/053605;

[0269] the selective androgen receptor modulator suitable for use hereinmay be LGD-2226 (Ligand);

[0270] the antiarrhythmic agents suitable for use herein includeβ-blockers as set out herein including sotalol and amioderome, calciumchannel blockers as set out herein including verapamil, nifedipine,amlodipine-besylate, and diltiazem, which may also be used incombination with a debrillator device such as a pace maker;

[0271] coenzyme Q sub. 10 such as disclosed in U.S. Pat. No. 5,316,765,4,933,165, 4,929,437;

[0272] an agent that upregulates type III endothelial cell nitric acidsyntase such as disclosed in WO 2000/003746;

[0273] a chondroprotective compound such as a polysulfatedglycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS),hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline orminocycline, such as disclosed in EP 970694;

[0274] a cyclooxygenase (COX)-2 inhibitor, such as celecoxib (Celebrex®(Searle)) or rofecoxib (Vioxx® (Merck)) or a glycoprotein IIa/IIIbreceptor antagonist such as disclosed in WO 99/45913 and tirofiban orabciximab;

[0275] a 5-HT reuptake inhibitor such as disclosed in WO 99/44609;

[0276] anti-anginal agents such as vasodilators, for example, isosorbidedinitrate, or nitroglycerin;

[0277] a growth hormone secretagogue such as disclosed in U.S.applications Ser. No. 09/662,448, filed Sep. 14, 2000, and U.S.Provisional application No. 60/203,335, filed May 11, 2000, and MK-677(Merck), Pfizer's CP-424391 and Lilly's LY 444,711;

[0278] anti-atherosclerosis agents such as ACAT inhibitors andlipoxygenase inhibitors as described herein and phospholipase A-2inhibitors such as S-3013 and SB-435,495 (which are alsoanti-inflammatory agents);

[0279] anti-infective agents such as quinolones, for example,ciprofloxacin, ofloxacin, and Tequin® (Bristol-Myers Squibb), macrolidessuch as erythromycin and clarithromycin (Biaxin® (Abbott)), andazithromycin (Zithromax (Pfizer)); or

[0280] an immunosuppressant (for use in transplantations) such ascyclosporine, mycophenolate mofetil, azathioprine and the like.

[0281] As used herein, the phrase “antineoplastic agent” refers tocompounds which prevent cancer cells from multiplying. In general, theantineoplastic agents used herein prevent cancer cells from multiplyingby: (1) interfering with the cell's ability to replicate DNA, or (2)inducing apoptosis in the cancerous cells.

[0282] Examples of antineoplastic agents which are suitable for use incombinations of this invention include, but are not limited to,microtuble-stabilizing agents such as the taxanes, for example,paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®),7-O-methylthio- methylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176),3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel(disclosed in U.S. Ser. No. 60/179,965 filed on Feb. 3, 2000, andexample 17 herein), C-4 methyl carbonate paclitaxel (disclosed in WO94/14787), the epothilone, such as epothilone A, epothilone B,epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B,[1S-[1R★, 3R★(E), 7R★, 10S★, 11R★, 12R★,16S★]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione (disclosed in WO 99/02514), [1S-[1R★,3R★(E), 7R★,10S★, 11R★, 12R★,16S★]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-di-hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabi-cyclo[14.1.0]-heptadecane-5,9-dione(disclosed in U.S. Pat. Ser. No. 09/506,481 filed on Feb. 17, 2000, andexamples 7 and 8 herein), and derivatives thereof; microtuble-disruptoragents; alkylating agents; anti-metabolites; epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes; biological responsemodifiers; growth inhibitors; hormonal/antihormonal therapeutic agents;and haematopoietic growth factors.

[0283] Other classes of antineoplastic agents suitable for use in themethod of the present invention include, but are not limited to, theanthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, discodermolide, the pteridinefamily of drugs, diynenes, aromatase inhibitors, and thepodophyllotoxins. Particularly useful members of those classes notpreviously mentioned include, for example, doxorubicin, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin orpodophyllotoxin derivatives such as etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, and the like. Other useful antineoplastic agents includeestramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin,tamoxifen, ifosfamide, melphalan, hexamethyl melamine, thiotepa,cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase,camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons, andinterleukins.

[0284] It will be appreciated that unless otherwise specified the dosageregiment for therapeutic agents used in combination with the compoundsof the invention will be as specified in the PDR.

[0285] In carrying out the method of the invention for treatinghypercholesterolemia, hyperlipidemia, hyperlipoproteinemia,hypertriglyceridemia, or atherosclerosis, and related diseases, orAlzheimer's disease or osteoporosis, or other disclosures as set outhereinbefore, a pharmaceutical composition will be employed containingthe compounds of structure I, with or without other cholesterol loweringagents, osteoporosis agents, Alzheimer's agents, antidiabetic agent(s)and/or antihyperlipidemic agent(s) and/or other type therapeutic agentsin association with a pharmaceutical vehicle or diluent. Thepharmaceutical composition can be formulated employing conventionalsolid or liquid vehicles or diluents and pharmaceutical additives of atype appropriate to the mode of desired administration, such aspharmaceutically acceptable carriers, excipients, binders and the like.The compounds can be administered to mammalian species including humans,monkeys, dogs, etc. by an oral route, for example, in the form oftablets, capsules, beads, granules or powders, or they can beadministered by a parenteral route in the form of injectablepreparations, or they can be administered intranasally or in transdermalpatches. Typical solid formulations will contain from about 0.1 to about500 mg of a compound of formula I. The dose for adults is preferablybetween 0.5 and 1,000 mg per day, which can be administered in a singledose or in the form of individual doses from 1-4 times per day and alsosingle dose once weekly (5 to 1000 mg).

[0286] A typical injectable preparation is produced by asepticallyplacing 250 mg of compounds of structure I into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

[0287] The following abbreviations are employed in the Examples andelsewhere herein:

[0288] Ph=phenyl

[0289] Bn=benzyl

[0290] i-Bu=iso-butyl

[0291] Me=methyl

[0292] Et ethyl

[0293] TMS=trimethylsilyl

[0294] FMOC=fluorenylmethoxycarbonyl

[0295] Boc=tert-butoxycarbonyl

[0296] Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0297] DIPEA=diisopropyl ethylamine

[0298] PTSH=N-phenylthiotetrazole

[0299] PPh₃=triphenylphosphine

[0300] NMO=methylmorpholine N-oxide

[0301] TPAP=tetrapropylammonium perruthenate

[0302] DEAD=diethyl azodicarboxylate

[0303] HOAc or AcOH=acetic acid

[0304] TFA=trifluoroacetic acid

[0305] Et₂NH=diethylamine

[0306] NMM=N-methyl morpholine

[0307] n-BuLi=n-butyllithium

[0308] Pd/C=palladium on carbon

[0309] PtO₂ =platinum oxide

[0310] MTBE=methyl t-butyl ether

[0311] DI water=dionized water

[0312] TEA=triethylamine

[0313] EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride(or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)

[0314] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0315] HOAT=1-hydroxy-7-azabenzotriazole

[0316] PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphoniumhexafluorophosphate

[0317] LiN(TMS)₂=Libis(trimethylsilyl)amide

[0318] DIBAL=diisobutylaluminum hydride

[0319] LDA=lithium diisopropylamide

[0320] DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

[0321] AcCN=acetonitrile

[0322] LiHMDS=lithium bis(trimethylsilyl)amide

[0323] NaHMDS=sodium bis(trimethylsilyl)amide

[0324] Red-AL=sodium bis(2-methoxyethoxy)aluminum hydride

[0325] mCPBA=m-chloro-p-benzoic acid

[0326] min=minute(s)

[0327] h or hr=hour(s)

[0328] L=liter

[0329] mL=milliliter

[0330] μL=microliter

[0331] g=gram(s)

[0332] mg=milligram(s)

[0333] mol=moles

[0334] mmol=millimole(s)

[0335] meq=milliequivalent

[0336] RT, rt=room temperature

[0337] sat or sat'd=saturated

[0338] aq.=aqueous

[0339] TLC=thin layer chromatography

[0340] HPLC=high performance liquid chromatography

[0341] LC/MS=high performance liquid chromatography/mass spectrometry

[0342] MS or Mass Spec=mass spectrometry

[0343] NMR=nuclear magnetic resonance

[0344] mp=melting point

[0345] Bp=boiling point

[0346] The following Examples represent preferred embodiments of theinvention. Unless otherwise indicated, all temperatures are in degreesCentigrade.

Example 1

[0347]

[0348] A mixture of polyphosphoric acid (82.9 g) and dry o-xylene (30ml) was heated to 105-110° C. in an oil bath, treated with a solution of4-phenoxybutyric acid (25 g, 0.137 mole) in dry o-xylene (110 ml) andstirred at 105-110° C. for 2 hours. The reaction mixture was cooled toroom temperature over a 2-hour period, poured into ice-water (180 ml),then extracted with ether (3×150 ml). The combined organic extracts(rust-colored) were washed with water (2×80 ml) and brine (80 ml), dried(anhydrous Na₂SO₄), filtered, evaporated to dryness and evaporated oncefrom hexanes (500 ml). The residue was dried in vacuo for 48 hours togive a reddish-brown syrup (27.19 g) which was divided into twoportions, chromatographing each portion on a silica gel column, (EM,2-¼″×10″) to give a light amber syrup (10.792 g). Trituration of animpure fraction with ether (3×25 mL) gave an additional 1.98 g ofproduct. Yield : 12.77 g, amber syrup; 58%. Rf 0.38 (Silica gel;EtOAc:Hexane-1:4; UV).

[0349] An oven-dried 3-neck 1-L flask equipped with temperature sensorprobe, 125-mL constant pressure addition funnel and septum was chargedwith dry CH₂Cl₂ (300 mL) and dry DMSO (20.9 mL, 0.2944 mol, 2.5 equiv)under argon atmosphere; cooled to -75° C. Oxalyl chloride (13.6 mL,0.156 mol, 1.32 equiv) was added neat via syringe dropwise over 15 min(temperature rose to −66° C.), and then let stir additional 15 min. Asolution of the alcohol2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acidt-butyl ester (30.66 g, 0.1178 mol, 1 equiv) in dry CH₂Cl₂ (80 mL) wasadded dropwise from the addition funnel over 30 min (temperature rose to−68° C. ). The resulting white mixture was stirred for 70 min at −76°C., then triethylamine (82 mL, 0.5889 mol, 5 equiv) was added dropwisefrom addition funnel over 35 min (temperature rose to −65° C. ), thenthe light yellow mixture was stirred vigorously at −76° C. TLC (SiO₂,20% EtOAc/CH₂Cl₂, Rf=0.52). After 30 min, the cooling bath was removedand the reaction was quenched by slowly adding cold 20% aq KH₂PO₄ (35mL), followed by cold H₂O (300 mL); and then let stir 15 min(temperature rose to −7° C. ). The reaction was poured into a 2-Lseparatory funnel and extracted with hexanes (500 mL). The organicextract was washed with cold 10% aq KH₂PO₄ (3×300 mL) and saturatedaqueous NaCl (300 mL). The organic was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give yellow oil. Purification bySiO₂ flash chromatography (10 cm×20 cm column) with 35:65 EtOAc/Hexanesafforded the title compound as a white solid (22.2 g, 0.0859 mol, 73%):¹H NMR (CDCl₃) δ 1.267-1.465 (m, 16H), 1.802 (dd, J=12.7 Hz, 2.2 Hz,1H), 2.290-2.464 (m, 2H), 4.314 (d, J=18.4 Hz, 2H), 9.555 (d, J=1.3 Hz,1H).

[0350] To a slurry of NaH (19.20 g, 480 mmol) and diethyl carbonate (80mL) in a 3-neck 1L round bottom flask at room temperature was added asolution of cyclopropyl methylketone (23.5 mL, 238 mmol) in Et₂O (30mL). Approximately 10% of the solution was added, and then 0.25 mL ofEtOH was added to the reaction slurry. Addition of the remaining ketonesolution continued with light gas evolution. After addition of all ofthe ketone solution, the reaction became quite exothermic with vigorousH₂ evolution. The reaction mixture was cooled periodically with anice-bath to keep the temperature around 35° C. to 50° C. After one hour,gas evolution had ceased and the reaction mixture was stirred at roomtemperature for 2h. The reaction mixture was cooled in an ice-bath,diluted with Et₂O (200 mL), and treated with 1 N HCl with some ice toadjust to around pH 3. The reaction mixture was extracted with Et₂O(3×150 mL). The Et₂O extracts were combined, washed with saturatedaqueous NaHCO₃ (200 mL), H₂O (200 mL) and brine (200 mL), and dried(Na₂SO₄) , filtered and concentrated under reduced pressure to give ayellow oil. The oil was distilled under vacuum to give the titlecompound as a colorless oil, 28.5 g, 77%. B.p.=94-96° C./8 mmHg.

[0351] To a stirred solution of part A(2) compound (28.24 g, 181 mmol)in benzene (128 mL) was added 4-fluoro-benzaldehyde (19.4 mL, 181 mmol),HOAc (0.31 mL, 5.4 mmol) and piperidine (1.8 mL, 18.2 mL). The reactionmixture was heated at reflux and azeotrope was collected with aDean-Stark trap. After 16 h, the reaction was cooled to roomtemperature, diluted with Et₂O (250 mL), washed with aqueous 0.5 N HCl,saturated aqueous NaHCO₃, H₂O and brine, and then dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashchromatography (1:10 EtOAc/hexane) gave the title compound as a lightyellow oil, 29 g, 61% yield.

[0352] A solution of compound of Part A (7.21 g, 40.9 mmol) in dry THF(5.0 ml) was added to a −78° C. solution of lithiumbis(trimethylsilyl)amide (1.0 M in THF; 49 ml, 49 mmol) in dry THF (25ml) and stirred at −78° C. under argon for 1 hour. The reaction mixturewas treated with a solution of Example 1 Part A(3) compound (7.15 g,27.3 mmoles), in dry THF, stirred at −78° C. for 30 minutes then at 0°C. for 30 minutes. The reaction mixture was quenched at 0° C. by thedropwise addition of glacial acetic acid (5 ml) and the resulting slurrywas stirred at room temperature for another 5 minutes then poured slowlyinto an ammonium chloride solution (25%, 140 ml). The bright yellowsolution was extracted with ether (2×100 ml) and the combined organicextracts were washed with water (2×25 ml) and brine (25 ml), dried(anhydrous Na₂SO₄), filtered, evaporated to dryness and dried in vacuoto give the crude product mixture as a yellow oil (17.16 g).

[0353] A mixture of crude Part B compound (17.0 g, 27.3 mmol), ammoniumacetate (9.34 g, 120 mmol) and copper acetate monohydrate (20.54 g, 101mmol) in glacial acetic acid (100 ml) was refluxed under argon for 19hours. The mixture was poured into an ice-cold solution of concentratedammonium hydroxide (85 ml) in water (170 ml) and the bright bluesolution was extracted with ether (3×200 ml). The combined organicextracts were washed with water (2×80 ml) and brine (80 ml), dried(anhydrous Na₂SO₄), filtered, evaporated to dryness, and dried in vacuo.The crude product (14 g, brown syrup) was chromatographed in twobatches, each on a silica gel column (EM, 2-¼″×10″) to give the desiredproduct as an off-white solid (4.161 g). An additional 931 mg of productwas obtained from chromatography of mixed fractions. Yield: 5.092 g, 46%from compound A). Rf 0.53 (Silica gel; EtOAc:Hexane-1:4; UV)

[0354] A solution of Part C compound (2.515 g, 6.23 mmol) in dry THF (30ml) was cooled to 0° C. (ice-water bath), treated dropwise with lithiumaluminum hydride (1.0 M in THF; 12.5 ml, 12.5 mmol), stirred at 0° C.for 30 minutes then at room temperature for 3 hours. The reactionmixture was cooled to 0° C. treated successively with water (0.5 ml),15% NaOH (0.5 ml) and water (1.5 ml), stirred at room temperature for 5minutes then diluted with ethyl acetate (50 ml). The slurry was filteredthrough a Celite® pad, washing the pad well with ethyl acetate (3×25ml). The clear filtrate was evaporated to dryness and dried in vacuo togive the title product. Yield: 2.386 g, white foam (100%). Rf 0.15(Silica gel; EtOAc:Hexane-1:4; UV).

[0355] A solution of Part D compound (2.27 g, 6.23 mmol) in drydichloromethane (45 ml) was cooled to 0° C. (ice-water bath) and treateddropwise with phosphorus tribromide (1.0 M in dichloromethane; 12.5 ml,12.5 mmol). The ice bath was removed and the reaction mixture wasstirred at room temperature for 30 minutes after which it was re-cooledto 0° C. and treated dropwise with saturated sodium bicarbonate (70 ml).The mixture was then warmed to room temperature and extracted with ethylacetate (2×100 ml). The combined organic extracts were washed with water(2×50 ml) and brine (50 ml), re-extracting each aqueous wash withdichloromethane (100 ml). The organic extracts were dried (anhydroussodium sulfate), filtered, evaporated to dryness and dried in vacuo togive the title product as a white solid. Yield: 2.503 g, (94%).m.p.=169-171° C. Rf 0.58 (Silica gel; EtOAc:Hexane-1:4; UV).

[0356] A solution of diethyl phosphite (0.88 ml, 6.83 mmoles) in dry THF(10 ml) was cooled to -10° C. (acetonitrile-dry ice bath), treated withsodium (bistrimethylsilyl)amide (1.0 M in THF; 6.7 ml, 6.7 mmol) andstirred at −10° C. for 30 minutes. The cooled solution was treated witha solution of Part E compound (2.41 g, 5.68 mmol) in dry THF (20 ml),stirred at −10° C. for 1.0 hour then quenched at −10° C. with water (14ml). The solution was extracted with ethyl acetate (2×75 ml) and thecombined organic extracts washed with 1.0 M hydrochloric acid (8.0 ml)and brine (10 ml), dried (anhydrous sodium sulfate), filtered,evaporated to dryness and dried in vacuo. The crude product (3.12 g,syrup) was chromatographed on a silica gel column (EM, 5.5 cm×12.5 cm)to give the title compound as a syrup. Yield: 2.34 g (85.5%). Rf 0.33(Silica gel; EtOAc-Hexane-1:1; UV).

[0357] A solution of Part F compound (2.29 g, 4.756 mmol) in dry THF (20ml) was cooled to −78° C., treated with 2.37 M n-butyllitium (2.41 ml,5.71 mmol) and stirred at −78° C. for 40 minutes. The solution wastreated dropwise via cannula with a −78° C. solution of Part A(1)compound (2.36 g, 9.15 mmol) in dry THF (10 ml), keeping both solutionsat −78° C. at all times. The reaction mixture was stirred at −78° C. for1.0 hr, −10° C. for 1.0 hr and at room temperature for 5 hr, quenchedwith 25% ammonium chloride solution (12 ml) then extracted with ethylacetate (2×100 ml). The combined organic extracts were washed with 25%ammonium chloride solution (12 ml) and brine (12 ml), dried (anhydroussodium sulfate), filtered, evaporated to dryness and dried in vacuo. Thecrude product yellow syrup was chromatographed on a silica gel column(EM, 2-¼″×10″) to afford the title compound as a syrup. Yield: 878 mg(32%). Rf 0.37 (Silica gel; EtOAc:Hexane-1:4; UV).

[0358] A solution of Part G compound (850 mg, 1.45 mmol) in drydichloromethane (20 ml) was cooled to 0° C. , treated withtrifluoroacetic acid (1.85 ml, 24 mmol), stirred at 0° C. for 5 minutes,then at room temperature for 4.5 hours. The reaction mixture was pouredslowly into a 1 L flask containing ethyl acetate (300 ml) and saturatedsodium bicarbonate (40 ml), rinsing the flask with ethyl acetate (50ml). The mixture was stirred well and the phases separated, washing theorganic phase with saturated sodium bicarbonate (25 ml) and brine (25ml). The organic phase was dried over anhydrous sodium sulfate,filtered, evaporated to dryness and dried in vacuo. The crude productmixture was chromatographed on a silica gel column (EM, 1.5″×12″) togive the desired compound as a syrup. Yield: 570 mg (83%). Rf 0.23(Silica gel; EtOAc:Hexane-1:1; UV)

[0359] A solution of Part H compound (550 mg, 1.17 mmol) in dry THF (10ml) was treated with 1.0 N NaOH (1.46 ml; 1.46 mmol) and stirred at roomtemperature for 10 minutes. The reaction mixture was evaporated todryness and the residual solid was dissolved in a mixture of water (8.7ml) and 1.0 N sodium hydroxide (70 ul). The solution was eluted on anSP207 column (Na+form; 1.5″×4″), eluting the column with water (200 ml),10% CH₃CN/H₂O (200 ml) , 20% CH₃CN/H₂O (100 ml) and 50% CH₃CN/H₂O (200ml). The desired fractions were combined and evaporated to dryness. Thesemi-solid obtained was dissolved in water (300 ml) and lyophilized togive the title compounds as a white solid. Yield: 583 mg (95%) Rf 0.48(Silica gel; CH₂Cl₂:MeOH:HOAc-18:1:1; UV).

[0360] Analysis for C₂₉H₂₆FNO₄Na·0.8 H₂O (MW=525.94):

[0361] Calc'd: C, 66.23; H, 5.29; N, 2.66; F, 3.61

[0362] Found: C, 66.37; H, 5.30; N, 2.62; F, 3.91

[0363] Alternate Procedure for Example 1 Part G Compound

[0364] The Example 1 Part E bromide (13.03 g, 0.027 mol, 1 equiv) andPh₂POEt (6.5 mL, 0.0297 mol, 1.1 equiv) were heated at reflux inanhydrous toluene (200 mL) under an argon atmosphere. The reactionbecame a thick yet stirrable white mixture after about 10 min. Thereaction was complete after 1 hr by tlc (SiO₂, 30% EtOAc/CH₂Cl₂, productRf=0.34). The mixture was cooled to 0°, and the white precipitate wascollected by vacuum filtration, washed with hexanes (2×50 mL), and driedin vacuo (14.8 g, 0.027 mol, 100%): HPLC (Shimadzu, YMC S-5 C18 4.6×50mm column, 4 min gradient @ 4 mL/min, UV detection 220 nM; start %B=50,final %B=100; A=10:90 MeOH/H₂O+0.2% H₃PO₄, B=90:10 MeOH/H₂O+0.2% H₃PO₄)R.T.=3.70 min (100%);

[0365]¹H NMR (CDCl₃) δ 0.712-0.760 (m, 2H), 1.10-1.14 (m, 2H),2.163-2.228 (m, 1H), 2.3211 (t, J=6.2 Hz, 2H), 3.850 (d, J=14 Hz, 2H),4.2568 (t, J=6.2 Hz, 2H), 6.779 (dd, J=8.3 Hz, 5.3 Hz, 2H), 6.9542 (t,J=8.3 Hz, 2H), 7.070 (d, J=7.9 Hz, 1H), 7.257 (t, J=7.5 Hz, 1H),7.334-7.421 (m, 9H), 7.469-7.521 (m, 2H), 7.822 (d, J=7.5 Hz, 1H); MSm/z 546 (M+H)⁺.

[0366] A flame-dried 250-mL flask was charged with Part G(1) compound(14.82 g, 27.2 mmol, 1 equiv), chased with anhydrous toluene (2×50 mL),dried over high-vacuum and filled with argon. THF (150 mL) was added andthe partial slurry was cooled to 0° C. A 2.5 M solution of n-BuLi inhexanes (11.4 mL, 0.0285 mol, 1.05 equiv) was added dropwise to thevigorously stirred mixture over a period of 40 min. The resulting greencolored solution was then stirred for 1 hr at 0° C. The aldehyde ExampleA(1) compound (8.42 g, 0.0326 mol, 1.2 equiv) in a flame-dried 500-mLflask (material previously chased with anhydrous toluene, 3×20 mL) underan argon atmosphere was dissolved in dry THF (75 mL) and cooled to −78°C. The phoshine anion solution was added dropwise to the aldehyde viacannula over a period of 45 min, then the dark blue colored solution wasstirred at −78° C. for 1.5 hr. The mixture was let warm to roomtemperature over a 2 hr period; the initially blue solution became adark brick-red color and finally a light orange color. TLC (SiO₂, 5%EtOAc/CH₂Cl₂, product Rf=0.37). The reaction was quenched withhalf-saturated aqueous NaCl (200 mL) and extracted with Et₂O (300 mL);the organic was washed with H₂O (2×100 mL) and saturated aqueous NaCl(100 mL). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. Purification by SiO₂ flash chromatography (10cm×25 cm) with 2% EtOAc/CH₂Cl₂ (2 L), 3% EtOAc/CH₂Cl₂ (2 L), 5%EtOAc/CH₂Cl₂ (1 L), 7% EtOAc/CH₂Cl₂ (1 L), and 10% EtOAc/CH₂Cl₂ (1 L)afforded Part G(2) compound (the same as Example 1 Part G compound) as awhite solid (11.13 g, 0.019 mol, 70%): HPLC (Shimadzu, YMC S-5 C184.6×50 mm column, 4 min gradient @ 4 mL/min, WV detection 220 nM; start%B=70, final %B=100; A=10:90 MeOH/H₂O+0.2% H₃PO₄, B=90:10 MeOH/H₂O+0.2%H₃PO₄) R.T.=4.36 min (100%);

[0367]¹H NMR (CDCl₃) δ 0.928-1.039 (m, 3H), 1.191-1.368 (m, 6H), 1.4384(s, 3H), 1.4483 (s, 9H), 2.225-2.431 (m, 3H), 2.4782 (t, J=6.2 Hz, 2H),4.188-4.334 (m, 2H), 4.3667 (t, 2H), 5.5846 (dd, J=16.2 Hz, 5.7 Hz, 1H),6.342 (d, J=16.2 Hz, 1H), 7.0663-7.1356 (m, 5H), 7.257 (t, J=7.5 Hz,1H), 7.3538 (t, J=7.5 Hz, 1H), 7.828 (d, J=7.5 Hz, 1H); MS (FAB) m/z 586(M+H)⁺.

Example 2

[0368]

[0369] A mixture of p-fluorobenzaldehyde (4.939 g, 0.039 mol, 1 equiv),ethyl isobutyrylacetate (6.495 g, 0.039 mol, 1 equiv), piperidine (0.395mL, 3.91 mmol, 0.1 equiv.), and glacial acetic acid (0.070 mL, 1.22mmol, 0.03 equiv) in anhydrous benzene (30 mL) was heated at reflux witha Dean-Stark trap to collect H₂O. After 20 hrs, the reaction was cooledto rt. The yellow reaction mixture was diluted with Et₂O (50 mL) andwashed with 0.5N aq HCl, satd. aq NaHCO₃, H₂O, and satd. aq NaCl. Theorganic extract was dried over anhydrous Na₂SO₄ vacuum filtered and thefiltrate concentrated by rotary evaporation in vacuo to yellow oil.Vacuum distillation afforded the desired product as a light yellow oil(8.575 g, 0.0324 mol, 83%): bp 107-115° C. (0.225 mm Hg);

[0370]¹H NMR (CDCl₃) δ 1.047 and 1.160 (d's, J=6.6 Hz, 6H, 1.4:1 ratio),1.260 and 1.296 (t's, J=7.1 Hz, 3H, 1:1.4 ratio), 2.674 and 3.140 (m's,J=7 Hz, 1H, 1.4:1 ratio), 4.245-4.324 (m, 2H), 7.010-7.074 (m, 2H),7.346-7.448 (m, 2H), 7.701 (s, 1H). MS (FAB) m/z 265 (M+H)⁺, 287(M+Na)⁺.

[0371] An oven-dried 250-mL 3-neck flask purged with argon was chargedwith anhydrous THF (30 mL) and lithium bis(trimethylsilyl)amide (1M inTHF, 57.9 mL, 0.058 mol, 1.8 equiv), then cooled to −78° C. in a dryice-acetone bath. A solution of Example 1 Part A compound (7.824 g,0.0482 mol, 1.5 equiv) in dry THF (6 mL) was added via cannula and theenolate allowed to generate over 1 hr at −78° C. Then a solution of PartA compound (8.50 g, 0.0322 mol, 1 equiv) in dry THF (6 mL) was added viacannula and the resulting amber solution stirred at −78° C. for 30 min,then at 0° C. for 30 min. The reaction was quenched with glacial aceticacid (6 mL), then poured into satd aq NH₄Cl. The mixture was extractedwith Et₂O (100 mL) and the ethereal extract was washed with H₂O (2×30mL) and satd aq NaCl. The organic was dried over anhydrous Na₂SO4,vacuum filtered and concentrated by rotary evaporation in vacuo to ayellow oil (17.19 g): MS (FAB) m/z 427 (M+H)⁺.

[0372] The crude Part B compound (17.19 g), NH₄OAc (11.Og, 0.142 mol,4.4 equiv), and Cu(OAc)₂ monohydrate (24.2 g, 0.119 mol, 3.7 equiv) weredissolved in glacial HOAc (120 mL) under argon and heated at gentlereflux for 20 hrs. The reaction was cooled to rt, then poured into anice cold solution of conc NH₄OH (100 mL) in H₂O (200 mL). The mixturewas extracted with Et₂O (200 mL+2×100 mL), then the combined etherealextracts was washed with H₂O (2×100 mL) and satd aq NaCl. The extractwas dried over anhydrous Na₂SO₄, vacuum filtered and concentrated byrotary evaporation in vacuo. The resulting brown oil was chased withhexanes to remove HOAc, followed by drying in vacuo Purification in twobatches on two SiO₂ flash columns (5 cm×22 cm) with 5% EtOAc/Hexanesafforded the product as a yellow oil which crystallized upon sitting(5.98 g, 0.0148 mol, 46% for two steps):

[0373]¹H NMR (CDCl₃) δ 0.959 (t, J=7 Hz, 3H) , 1.164 and 1.359 (d's, J=7Hz, 6H, 1:4 ratio), 2.557 (t, J=6.2 Hz, 2H), 2.897 and 3.146 (mls, J=7Hz, 1H, 1:4 ratio), 4.006 (q, J=7 Hz, 2H), 4.418 (t, J=6.2 Hz, 2H),6.710-7.578 (m, 7H), 7.898 (d, J=7.5 Hz, 1H); MS (ESI+Q) m/z 406 (M+H)⁺.

[0374] Part C compound (5.78 g, 0.0143 mol, 1 equiv) was dissolved indry THF (70 mL) under argon and cooled to 0° C. A solution of LiAlH₄ inTHF (1M, 28.5 mL, 0.0285 mol, 2 equiv) was added slowly. The reactionwas stirred at rt for 2 hrs, followed by 25 min at reflux. TLC (SiO₂, 5%EtOAc/CH₂Cl₂, Rf=0.24) . The reaction was cooled to 0° C., thencarefully quenched with H₂O (2.3 mL) , 15% aq NaOH (2.3 mL), and H₂O(4.7 mL). The white mixture was stirred at rt for 10 min, then vacuumfiltered and the solid washed with EtOAc. The filtrate was concentratedby rotary evaporation in vacuo to a yellow oil. Purification on a SiO₂flash column (5cm×20 cm) with a gradient of 4% to 8% EtOAc/CH₂Cl₂afforded the product as a white solid (4.082 g, 0.0112 mol, 79%):

[0375]¹H NMR (CDCl₃) δ 1.402 (d, J=6.6 Hz, 6H), 2.463 (t, J=6.2 Hz, 2H),3.532 (m, J=6.6 Hz, 1H), 4.382 (t, J=6.2 Hz, 2H), 4.461 (d, J=5.3 Hz,2H), 7.097 (d, J=7.9 Hz, 1H), 7.168 (t, J=8.8 Hz, 2H), 7.233-7.397 (m,4H), 7.929 (d, J=7.5 Hz, 1H); MS (ESI+Q)m/z 364 (M+H)⁺.

[0376] The Part D alcohol (3.066g, 8.437 mmol, 1 equiv), dissolved indry CH₂Cl₂ (60 mL) under argon at 0° C., was treated by dropwiseaddition of a 1M solution of PBr₃ in CH₂Cl₂ (16.9 mL, 16.9 mmol, 2equiv). The reaction was stirred at rt for 30 min, at which time thereaction was recooled to 0° C. and treated with satd aq NaHCO₃ (90 mL).The mixture was diluted with CH₂Cl₂ (50 mL) , the layers were separated,and the organic washed with H₂O (2×50 mL) and satd aq NaCl (50 mL). Theorganic was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. TLC (SiO₂, 5% EtOAc/CH₂Cl₂, Rf=0.69). The residue was purified bySiO₂ flash chromatography (3.8 cm×15 cm column) with CH₂Cl₂ to obtainproduct as white solid (2.97 g, 6.97 mmol, 83%):

[0377]¹H NMR (CDCl₃) δ 1.403 (d, J=6.6 Hz, 6H), 2.430 (t, J=6.2 Hz, 2H),3.459 (m, J=6.6 Hz, 1H), 4.290 (s, 2H), 4.356 (t, J=6.2 Hz, 2H), 7.087(d, J=7.9 Hz, 1H), 7.183 (t, J=7.5 Hz, 2H), 7.263-7.397 (m, 4H), 7.910(d, J=7.5 Hz, 1H); MS (ESI+Q) m/z 426/428 (M+H)⁺.

[0378] The Part E bromide (2.97 g, 6.967 mmol, 1 equiv) and ethyldiphenylphosphinite (1.7 mL, 7.663 mmol, 1.1 equiv) were heated atreflux under argon for 1.5 hrs. TLC (SiO₂, 30% EtOAc/CH₂Cl₂, productRf=0.47). The reaction was cooled in an ice bath, then the solidcollected by vacuum filtration in Buchner funnel; the solid was washedwith small volumes of toluene, followed by hexanes. This affordedproduct as white solid (3.48 g, 6.35 mmol, 91%):

[0379]¹H NMR (CDCl₃) δ 1.256 (d, J=6.6 Hz, 6H), 2.334 (t, J=6 Hz, 2H),3.33 (m, 1H), 3.716 (d, J=13.6 Hz, 2H), 4.252 (t, J=6 Hz, 2H), 6.767 (brt, J=5.3 Hz, 2H), 6.895 (t, J=8.5 Hz, 2H), 7.072 (d, J=7.9 Hz, 1H),7.284 (t, J=7.4 Hz, 1H), 7.320-7.420 (m, 9H), 7.460-7.520 (m, 2H), 7.929(d, J=7.4 Hz, 1H); MS (ESI+Q) m/z548 (M+H)⁺.

[0380] An oven-dried 50-mL flask charged with the Part Fdiphenylphosphine oxide (1.00 g, 1.826 mmol, 1 equiv) was chased withanhydrous toluene (3×5 mL), dried on hi-vacuum, and filled with argon.The dry solid was dissolved in dry THF (10 mL) and the resultingsuspension cooled to 0° C. nBuLi solution (Aldrich, titrated withdiphenylacetic acid: 2.4 M in hexanes; 0.80 mL, 1.92 mmol, 1.05 equiv)was added slowly dropwise over 20 min. The resulting dark amber-coloredsolution was allowed to stir at 0° C. for 1 hr. The Example 1 A(1)aldehyde (0.566 g, 2.192 mmol, 1.2 equiv) in an oven-dried 100-mL flask(material previously chased with anhydrous toluene (3×5 mL) and dried invacuo) under argon atmosphere was dissolved in dry THF (5 mL) and cooledto −78° C. The anion solution was added via cannula to the aldehydesolution over a period of 25 min, then the dark green-colored solutionwas stirred at −78° C. for 1.5 hrs. The acetone/dry ice bath was thenremoved and the reaction allowed to slowly warm to room temperature; theinitially green solution became an orange mixture. After 2 hrs, thereaction was quenched with half-satd aq NaCl (60 mL), extracted withEt₂O (100 mL), then washed the organic with H₂O and satd aq NaCl.Purification by SiO₂ flash chromatography (3.8 cm×15 cm column) affordedthe product as a white foam (556 mg, 0.946 mmol, 52%). Also recoveredunreacted diphenylphosphine oxide (445 mg, 0.8127 mmol):

[0381]¹H NMR (CDCl₃) δ 0.890 (q, 1H), 1.323-1.462 (m, 21H), 1.595 (d,1H), 2.249 (dd, J=15.4 Hz, 6.2 Hz, 1H), 2.403 (dd, J=15.4 Hz, 7.0 Hz,1H), 2.516 (t, J=6.2 Hz, 2H), 3.406 (m, 1H), 4.197-4.295 (m, 2H), 4.407(m, 2H), 5.288 (dd, J=16.2 Hz, 5.7 Hz, 1H), 6.327 (dd, J=16.2 Hz, 1.3Hz, 1H), 7.076-7.142 (m, 5H), 7.277-7.399 (m, 2H), 7.943 (d, J=7.5 Hz,1H); MS (ESI+Q) m/z 588 (M+H)⁺.

[0382] The Part G compound (0.230 g, 0.391 mmol) was dissolved in dryCH₂Cl₂ (5 mL) under an argon atmosphere and cooled to 0° C.Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred atrt for 6 hrs. TLC (Sio₂, 20% EtOAc/CH₂Cl₂, Rf=0.31) . The reactionsolution was transferred to a separatory funnel and treated with satd aqNaHCO₃ (25 mL), extracted with EtOAc (100 mL), and the organic washedwith satd aq NaHCO₃ and satd aq NaCl. The organic was dried overanhydrous Na₂SO₄ filtered and concentrated by rotary evaporation invacuo. The residue was purified by SiO₂ flash chromatography (1.9 cm×15cm column) to afford the product as a white solid (160 mg, 0.338 mmol,86%):

[0383]¹H NMR (CDCl₃) δ 1.304 (d, J=6.6 Hz, 6H), 1.442-1.690 (m, 2H),2.476-2.678 (m, 4H), 3.339 (m, 1H), 4.157 (m, 1H), 4.389 (t, J=6.2 Hz,2H), 5.076 (m, 1H), 5.320 (dd, J=16.2 Hz, 10.1 Hz, 1H) , 6.489 (d,J=16.2 Hz, 1H) , 7.06-7.16 (m, 5H), 7.281 (t, 1H), 7.368 (t, 1H), 7.914(d, J=7.5 Hz, 1H); MS (ESI+Q) m/z 474 (M+H)⁺.

[0384] The Part H lactone (148 mg, 0.3125 mmol, 1 equiv) was dissolvedin THF (3 mL), treated with 1N aq NaOH (0.391 mL, 0.3907 mmol, 1.25equiv), and stirred at rt. TLC (SiO₂, 0.5:0.5:9 HOAc/MeOH/CH₂Cl₂,Rf=0.25). After 30 min, the solvents were removed by rotary evaporationin vacuo and the residue dried on hi-vacuum. A SP207 Na-form resincolumn (1.9 cm×10 cm bed) was prepared as follows: the resin was pouredinto a glass chromatography column equipped with fritted disc support,the resin was washed with satd aq NaHCO₃ (15 mL), satd aq NaCl (15 mL),and DI H₂O (100 mL, Milli-Q). The residue was taken up in Milli-Q DI H₂O(5 mL), applied to column, and eluted with Milli-Q DI H₂O (100 mL), 10%AcCN/H₂O (60 mL), and 25% AcCN/H₂O (125 mL). Product-containingfractions were combined and concentrated by rotary evaporation in vacuoto a small volume, then transferred to a 40-mL lyophilization jar, usingadditional H₂O to rinse out flask. The contents of the jar were frozenin an acetone-dry ice bath and lyophilized to afford the product as awhite lyophilate (148 mg, 0.288 mmol, 92%):

[0385]¹H NMR (DMSO-d₆) δ 0.90-1.00 (m, 1H), 1.20-1.35 (m, 7H), 1.727(dd, J=14.9 Hz, 7.9 Hz, 1H), 1.955 (dd, J=14.9 Hz, 4 Hz, 1H) , 2.399 (t,J=6.2 Hz, 2H) , 3.424-3.490 (m, 2H), 4.00-4.10 (m, 1H), 4.386 (t, J=6.2Hz, 2H), 4.954 (br s, 1H), 5.354 (dd, J=16.2 Hz, 5.3 Hz, 1H), 6.297 (d,J=16.2 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.20-7.46 (m, 7H), 7.802 (dd,J=7.9 Hz, 1.8 Hz, 1H); MS (ESI+Q) m/z 492 (M+H)⁺;

[0386] Anal. Calcd for C₂₉H₂₉FNO₅Na H₂O:

[0387] C, 65.53; H, 5.88; N, 2.64.

[0388] Found: C, 65.46; H, 5.70; N, 2.52.

Example 3

[0389]

[0390] The Example 2 Part G compound (200 mg, 0.3403 mmol, 1 equiv) washydrogenated at 45 psi H₂ in anhydrous MeOH (30 mL) with 10% Pd-C (40mg, 20 wt %) for 2 hrs. The catalyst was washed with small portions ofMeOH and the filtrate was concentrated by rotary evaporation in vacuo.The residue was purified by SiO₂ flash chromatography (2.5 cm×13 cm)with 3% EtOAc/CH₂Cl₂ to afford the product as a white foam (193 mg,0.3273 mmol, 96%): HPLC (Shimadzu YMC S-5 C18 4.6×50 mm column, 4 mingradient @ 4 mL/min, UV detection 220 nM; start %B=60, final %B=100;A=10:90 MeOH/H₂O+0.2% H₃PO₄) R.T.=4.35 min (100%);

[0391]¹H NMR (CDCl₃) δ 0.902 (q, J=12.3 Hz, 1H), 1.27-1.60 (m, 24 H),2.212 (dd, J=15.4 Hz, 6.2 Hz, 1H), 2.25-2.42 (m, 4 H), 2.50-2.60 (m,1H), 3.336 (m, 1H), 3.599 (m, 1H), 4.10-4.20 (m, 1H), 4.328 (t, J=6.2Hz, 2H), 7.067 (d, J=7.9 Hz, 1H), 7.1416 (d, J=6.6 Hz, 4H), 7.265 (t,J=7.5 Hz, 1H), 7.340 (t, J=7.5 Hz, 1H), 7.901 (d, J=7.5 Hz, 1H); MS(ESI+Q) m/z 590 (M+H)⁺.

[0392] Part A compound (258 mg, 0.4375 mmol) was dissolved in dry CH₂Cl₂(5 mL) under argon, cooled to 0° C. and treated with trifluoroaceticacid (0.5 mL). Stirring was continued at room temperature for 7 hrs, atwhich time the reaction was complete by HPLC. Saturated aqueous NaHCO₃(25 mL) was added to the reaction, the reaction was diluted with EtOAc(100 mL), and the layers separated. The organic was washed withsaturated aqueous NaHCO₃ and saturated aqueous NaCl, then dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification bySiO₂ flash chromatography (1.9 cm×15 cm) with 20% EtOAc/CH₂Cl₂ affordeda white foam (163 mg, 0.343 mmol, 78%): HPLC (Shimadzu, YMC S-5 C184.6×50 mm column, 4 min gradient @ 4 mL/min, UV detection 220 nM; start%B=0, final %B=100; A=10:90 MeOH/H₂O+0.2% H₃PO₄, B=90:10 MeOH/H₂O+0.2%H₃PO₄) R.T.=3.81 min (94.6%);

[0393]¹H NMR (CDCl₃) δ 1.37 (d, J=6.6 Hz, 6H), 1.45-1.85 (m, 4 H),2.40-2.75 (m, 6H), 3.327 (m, 1H), 4.285 (br s, 1 H), 4.350 (t, J=6.2 Hz,2H), 4.49 (m, 1H), 7.093 (d, J=7.9 Hz, 1H), 7.181 (d, J=7.0 Hz, 4H),7.291 (t, J=7.5 Hz, 1H), 7.3697 (t, J=7.5 Hz, 1H), 7.912 (d, J=7.5 Hz,1H); MS (ESI+Q) m/z 476 (M+H)⁺.

[0394] Part B compound (149 mg, 0.3133 mmol, 1 equiv) was dissolved inTHF (3 mL) and 1N aqueous NaOH (0.392 mL, 0.3916 mmol, 1.25 equiv) andstirred at room temperature for 30 min. The solvent was removed byrotary evaporation in vacuoand the residue was dried under high-vacuum.An SP207 resin column (1.9 cm×10 cm ) was prepared as follows: resin waspoured into a glass chromatography column equipped with fritted discsupport and the resin was washed sequentially with saturated aqueousNaHCO₃ (15 mL), saturated aqueous NaCl (15 mL), and Milli-Q H₂O (100mL). The dried residue was taken up in Milli-Q H₂O (8 mL) and carefullyapplied to top of the column. The column was eluted with Milli-Q H₂O(100 mL), 10% AcCN/H₂O (60 mL), 20% AcCN/H₂O (60 mL), and 25% AcCN/H₂O(100 mL). Product-containing fractions were combined and concentrated byrotary evaporation to a small volume, and transferred to a 40-mLlyophilization jar. The contents were frozen in acetone-dry ice bath andlyophilized. This afforded the product as a white lyophilate (149 mg,0.289 mmol, 92%): HPLC (Shimadzu, YMC S-5 C18 4.6×50 mm column, 4 mingradient @ 4 mL/min, UV detection 220 nM: start %B=0, final %B=100;A=10:90 MeOH/H₂O +0.2% H₃PO₄, B=10:90 MeOH/H₂O+0.2% H₃PO₄) R.T.=3.58 min(92.9%);

[0395]¹H NMR (DMSO-d6) δ 1.048-1.105 (m, 1H), 1.232-1.50 (m, 9 H), 1.750(dd, J=14.9 Hz, 8.3 Hz, 1H), 1.966 (dd, J=14.9 Hz, 4.0 Hz, 1H),2.298-2.356 (m, 3H), 3.335-3.424 (m, 2 H), 3.616-3.656 (m, 1H), 4.3166(t, J=6.2 Hz, 2H), 4.711 (br s, 1H), 7.098 (d, J=7.9 Hz, 1H), 7.276-7.43(m, 6H), 7.773 (d, J=7.5 Hz, 1H); MS (ESI+Q) m/z 494 (M+H)⁺for acidform.

[0396] The following Examples may be prepared employing procedures setout herein and in the working Examples.

Example 27

[0397]

[0398] Following the procedure outlined in reaction Scheme 5 and thedescription thereof, the Example 27 aldehyde is obtained.

[0399] An example of a typical preparation of the aldehyde is set outbelow.

[0400] To a 500 mL round bottom flask equipped with a magnetic stirrerand a nitrogen inlet was charged compound (17) (Scheme 5)

[0401] (50 g, 128.4 mmol) (prepared as described in Example 2 Parts A, Band C except methyl isobutyryl acetate is substituted for ethylisobutyryl acetate) and toluene (170 mL). The mixture is stirred at20-25° C. until a clear solution is obtained. A solutin of 65% Red-Al intoluene (57.8 mL, 192.6 mmol) is added and the reaction mixture isheated to 80° C. until complete as determined by HPLC. The reactionmixture is cooled to ˜20° C. and quenched by pouring it into cold (0-5°C. ) 20% HCl (495 mL). Phases are separated and the spent toluene phaseis discarded. The pH of the aqueous phase is adjusted from <0 to 4-5with 10N NaOH. Ethyl acetate (500 mL) is added and the pH adjustmentcontinued to 7-8. The phases are separated. The aqueous phase isextracted with additional ethyl acetate (2×500 mL). The combined richethyl acetate solution is washed with water (3×250 mL) and concentratedunder reduced pressure to ˜465 mL. This solution is carried through tothe next oxidation step.

[0402] The rich ethyl acetate solution is charged from above into athree neck 1-L flask equipped with mechanical stirring, temperaturecontroller, and addition funnel and cooled to 0-5° C. To the slurry,potassium bromide (1.53 g, 12.8 mmol) and TEMPO(2,2,6,6-tetramethyl-l-piperidinyloxy) (0.20 g, 1.28 mmol) are added.The pH of NaOCl (sodium hypochlorite) solution (212.1 mL) is adjusted to˜9.1 and added to the slurry at a rate such that the temperatureremained at 0-5° C. Stirring is continued at 0-5° C. until the reactionis complete as determined by HPLC. The aqueous phase is extracted withEtOAc (2×200 mL). The combined rich organic phase is washed with a 1:1solution of sat. aq. Na₂S₂O₃ (sodium thiosulfate) (75 mL) and water (75mL) followed by wash of the rich organic phase with 1N NaOH (250 mL).The rich organic phase is washed with water (250 mL) and concentrated to˜100 mL under reduced pressure. Isopropanol (IPA) (400 mL) is added andthe resulting mixture is heated to reflux (80-85° C.). The solution isdistilled to a volume of ˜250 mL. Water (50 mL) is added and the crystalslurry is stirred at 70-80° C. for 1 h then allowed to cool to 20-25° C.over at least 1 h. The slurry is held at 20-25° C. for at least 1 hbefore collecting the solid by filtration on a Buchner funnel. The cakeis washed with cold (0° C.) IPA/water (4:1) (2×50 mL) and dried to aconstant weight under vacuum at 40° C. to afford title aldehyde.

Example 28

[0403]

[0404] A. Preparation of Sulfide (15)

[0405] To a 250 mL flask was charged Kaneka alcohol (12)(Scheme 6) (10.0g, 38.41 mmol), methylene chloride (100 mL), and triethylamine (11.75mL, 84.51 mmol) and cooled to −30° C. Triflic anhydride (7.11 mL, 42.25mmol) was added via a syringe at a rate to maintain the temperature at−35 to -25° C. , ˜15 min. The reaction mixture was stirred at −30° C.for ˜30 min and checked for disappearance of Kaneka alcohol by TLC. Aslurry of 1-phenyl-1H-tetrazole-5-thiol (7.19 g, 40.34 mmol) inmethylene chloride (50 mL) was added to the triflate solution. After thereaction was complete, water(100 mL) was added and the mixture wasstirred for ˜5 min. The phases were separated and the aqueous phase wasdiscarded. The rich organic phase was washed with water (100 mL) for ˜5min and phases separated. The rich organic phase was washed withsaturated NaHCO₃ (100 mL) for ˜15 min and phases separated. The richorganic phase was concentrated to ˜50 mL. The solution was taken to thenext step for further transformation.

[0406] IPA (150 mL) was added to the Part A sulfide solution from theabove step. The solution was cooled to 0-5° C. To the stirred solutionof sulfide, a solution of (NH₄)₆MO₇O₂₄·4H₂O (ammonium heptamolybdatetetrahydrate) (4.75 g, 3.84 mmol) in 30% H₂O₂ (hydrogen peroxide) wasadded dropwise during ˜15 min, maintaining the temperature of thesolutin at 0-5° C. The conversion of sulfide to sulfone was monitored byHPLC ˜24 h. After completion of the reaction, methylene chloride wasdistilled out. The pot temperature was maintained at not more than 25°C. The crystal slurry was distilled to a volume of ˜230 mL with IPA andthe resulting slurry was stirred for at least 1 h at 20-22° C. The solidwas collected by vacuum filtration, the cake washed with IPA/water (4:1,25 mL) followed by drying under vacuum at 40° C. to constant weightaffording 12.8 g (74%) of the title sulfone as a white crystallinesolid.

Example 29

[0407]

[0408] Following the procedure set out in reaction Scheme 5 and thedescription thereof, the Example 27 pyridine derivative and the Example28 sulfone are employed to prepare the title compound.

[0409] An example of a typical preparation of the Example 29 compound isset out below.

[0410] A_(n) N₂ purged 250 mL 3-neck rb flask is charged with Example 27pyridine derivative (18) (5 g, 13.9 mmol), Example 28 sulfone (16) (6.9g, 15.3 mmol) and THF (75 mL). The stirred solution is cooled to −74 to−78° C. Slowly a 1M solution of LiHMDS (lithiumbis(trimethylsilyl)amide) (15.3 mL, 15.3 mmol) in THF is charged at arate such that the temperture remained between −70 and −78° C. Afteraddition of the base is complete, the reaciton mixture is warmed to˜−45° C. over ˜15 minutes. The stirred reaction is quenched at −70° C.by slow addition of sat. aq. NH₄Cl (7.5 mL) solution and water (38 mL).The dry ice bath is removed and the solution is warmed to 20-25° C. fromthe reaction mixture. Ethyl acetate (50 mL) is added, the mixtureagitated, and layers separated. The organic layer is washed withsaturated sodium bicarbonate solution (2×38 mL) followed by brine (25mL) and concentrated to a volume of 50 mL. Acetonitrile (50 mL) is addedand the solution is concentrated to a volume of 50 mL. This step isrepeated. Water (˜5−6 mL) is slowly added to the hot solution (60-70° C.) until the cloud point is reached. The thin slurry is held for 30 minat high temperature and then slowly cooled over several hours withstirring. The product is filtered, cake is washed with a 5:1 mixture ofacetonitrile and water, and dried to afford the title compound.

Example 30 Preparation of the final compound

[0411]

[0412] Following the procedure of Example 3 Parts B and C, the Example29 compound is employed to prepare the title compound in the form of thesodium salt.

What is claimed is:
 1. A compound having the structure

wherein X is O, S or NR;

n is 0 or 1; R₁ and R₂ are the same or different and are independentlyselected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl,heteroaryl or cycloheteroalkyl; R₃ is H or lower alkyl; R₄ is H,halogen, CF₃, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, orcyano; R₇ is H, alkyl, aryl, alkanoyl, aroyl or alkoxycarbonyl; R₈ is Hor lower alkyl; R₉ and R₁₀ are the same or different and areindependently selected from H or alkyl, or R₉ and R₁₀ may be takentogether with the carbon or carbons to which they are attached to form a3 to 7 membered carbocyclic ring; and represents a single bond or adouble bond (which may be cis or trans); and including pharmaceuticallyacceptable salts thereof (where R₃ is H), esters thereof, prodrug estersthereof, and all stereoisomers thereof.
 2. The compound as defined inclaim 1 wherein is a double bond which is trans.
 3. The compound asdefined in claim 1 wherein Z is in the form of a pharmaceuticallyacceptable basic salt.
 4. The compound as defined in claim 1 in the formof a pharmaceutically acceptable acid addition salt.
 5. The compound asdefined in claim 1 wherein R₁ and R₂ are independently selected fromalkyl, cycloalkyl and aryl; R₄ is H or halogen; n is o; and X is O. 6.The compound as defined in claim 1 wherein R₁ is aryl, R₂ is alkyl orcycloalkyl; R₄ is H; n is o; X is O; and is a trans double bond, in theform of a free acid or an alkali or alkaline earth metal salt or anamino acid salt.
 7. The compound as defined in claim 6 wherein R₁ isphenyl which contains 1 or 2 substituents, R₂ is alkyl or cycloalkyl; R₄is H; X is O; and is a trans double bond, in the form of a free acid oran alkali or alkaline earth metal salt or an amino acid salt.
 8. Thecompound as defined in claim 7 wherein R₁ is 4-fluorophenyl,4-fluoro-3-methylphenyl, or 3,5-dimethylphenyl; and R₂ is isopropyl,t-butyl or cyclopropyl.
 9. The compound as defined in claim 1 wherein Zhas the structure


10. The compound as defined in claim 1 having the structure

or an alkali or alkaline earth metal salt thereof or an amino acid saltor an acid addition salt via the pyridine of the corresponding δlactone, wherein R₅ and R₆ are the same or different and areindependently selected from H, halogen or alkyl and R₂ is aikyl orcycloalkyl.
 11. The compound as defined in claim 10 wherein R₅ and R₆are H and 4-fluoro; H and 4-fluoro-3-methyl or 3,5-dimethyl; and R₂ isisopropyl, t-butyl or cyclopropyl.
 12. The compound as defined in claim1 having the structure

wherein R₃ is H or an alkali or alkaline earth metal or an amino acidsalt or other pharmaceutically acceptable salt, or the internal lactonethereof.
 13. A compound of the structure

wherein R₃ is H or an alkali or alkaline earth metal ion or an aminoacid, or the internal lactone thereof.
 14. The compound as defined inclaim 13 wherein R₃ is an alkali metal.
 15. The compound as defined inclaim 14 in the form of the sodium salt.
 16. A pharmaceuticalcomposition comprising a compound as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 17. A pharmaceuticalcombination comprising the HMG CoA reductase inhibitor compound asdefined in claim 1 and one or more hypolipidemic agents orlipid-lowering agents, or lipid agents, or lipid modulating agents,and/or one or more other types of therapeutic agents includingantidiabetic agents, anti-obesity agents, antihypertensive agents,platelet aggregation inhibitors, anti-dementia agents, anti-Alzheimer'sagents, anti-osteoporosis agents, and/or hormone replacement therapeuticagents, and/or other cardiovascular agents (including anti-anginalagents, anti-arrhythmic agents, anti-atherosclerosis agents,anti-inflammatory agents, anti-arthritis agents, anti-platelet agents,anti-heart failure agents), anti-cancer agents, anti-infective agents,hormone replacement agents, growth hormone secretagogues, selectiveandrogen receptor modulators, and/or immunomodulatory agents.
 18. Thecombination as defined in claim 17 wherein the hypolipidemic agent orlipid-lowering agent or other lipid agent or lipid modulating agent oranti-atherosclerotic agent, which is employed comprises 1,2,3 or moreMTP inhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, PPAR a agonists, PPAR dual α/γagonists, PPAR δ agonists, ACAT inhibitors, lipoxygenase inhibitors,cholesterol absorption inhibitors, ileal Na⁺/bile acid cotransporterinhibitors, upregulators of LDL receptor activity, cholesteryl estertransfer protein inhibitors, bile acid sequestrants, or nicotinic acidand derivatives thereof, ATP citrate lyase inhibitors, phytoestrogencompounds, an HDL upregulators, LDL catabolism promoters, antioxidants,PLA-2 inhibitors, antihomocysteine agents, HMG-CoA synthase inhibitors,lanosterol demethylase inhibitors, or sterol regulating element bindingprotein-I agents.
 19. The pharmaceutical combination as defined in claim17 comprising said HMG CoA reductase inhibiting compound and anantidiabetic agent.
 20. The combination as defined in claim 19 whereinthe antidiabetic agent which may be optionally employed is 1,2,3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, which may include biguanides,sulfonyl ureas, PTP-1B inhibitors, aldose reductase inhibitors,glucosidase inhibitors, PPAR γ agonists, PPAR α agonists, PPAR δantagonists or agonists, aP2 inhibitors, PPAR α/γ dual agonists,dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogenphosphorylase inhibitors, and/or meglitinides, insulin, and/orglucagon-like peptide-1 (GLP-1) or a mimetics thereof.
 21. Thecombination as defined in claim 20 wherein the antidiabetic agent is 1,2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide,chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone,troglitazone, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501,NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide,KAD1129, AR-H039242, GW-409544, KRP297, AC2993, LY315902, P32/98 and/orNVP-DPP-728A.
 22. The combination as defined in claim 17 wherein the HMGCoA reductase inhibiting compound is present in a weight ratio to thelipid-lowering agent or antidiabetic agent within the range from about0.001:1 to about 100:1.
 23. The combination as defined in claim 17wherein the other type of therapeutic agent which may be optionallyemployed is 1, 2, 3 or more of an anti-obesity agent which is a beta 3adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine)reuptake inhibitor, an aP2 inhibitor, a thyroid receptor beta drug, ananorectic agent, a PTP-1B inhibitor, a CCKA agonist, a neuropeptide Yantagonist, a melanocortin-4-receptor agonist, a PPAR modulator which isa PPAR γ antagonist, PPAR α agonist, and/or PPAR δ antagonist, a leptininhibitor such as a leptin receptor activator, a fatty acid oxidationupregulator or inducer.
 24. The combination as defined in claim 23wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355,CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine, and/or mazindol, P57 or CP-644673 (Pfizer).
 25. Thecombination as defined in claim 17 wherein the lipid modulating agent isan MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor and the otherlipid agent is a cholesteryl ester transfer protein inhibitor.
 26. Thecombination as defined in claim 25 wherein the lipid modulating agent ispravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin,fluvastatin, pitavastatin, rosuvastatin, fenofibrate, gemfibrozil,clofibrate, avasimibe, TS-962, MD-700, cholestagel, niacin, and/orLY295427.
 27. The combination as defined in claim 17 wherein theantihypertensive agent employed is an ACE inhibitor, angiotensin IIreceptor antagonist, NEP inhibitor, a NEP/ACE inhibitor, a calciumchannel blocker, a T-channel calcium antagonist, a β-adrenergic blocker,a diuretic, a α-adrenergic blocker, a dual action receptor antagonist(DARA), or a heart failure drug.
 28. The combination as defined in claim27 wherein the antihypertensive agent is an ACE inhibitor which iscaptopril, fosinopril, enalapril, lisinopril, quinapril, benazepril,fentiapril, ramipril or moexipril; an NEP/ACE inhibitor which isomapatrilat, gemopatrilat, or CGS 30440; an angiotensin II receptorantagonist which is irbesartan, losartan or valsartan; amlodipinebesylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol, orclonidine HCl, carvediol, atenolol, hydrochlorothiazide, torasemide,furosemide, spironolactone or indapamide.
 29. The combination as definedin claim 17 wherein the HMG CoA reductase inhibitor is in combinationwith an ACE inhibitor or a NEP/ACE inhibitor.
 30. The combination asdefined in claim 17 wherein the HMG CoA reductase inhibitor is incombination with an ACE inhibitor which is rampipril.
 31. Thecombination as defined in claim 17 wherein the HMG CoA reductaseinhibitor is in combination with a NEP/ACE inhibitor which isomapatrilat or gemopatrilat.
 32. The combination as defined in claim 17wherein the HMG CoA reductase inhibitor is in combination with aplatelet aggregation inhibitor.
 33. The combination as defined in claim32 wherein the platelet inhibitor is clopidogrel.
 34. The combination asdefined in claim 32 wherein the platelet inhibitor is clopidogrel,aspirin or a combination of clopidogrel and aspirin.
 35. The combinationas defined in claim 17 wherein the platelet aggregation inhibitor isaspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, abciximab,tirofiban, eptifibatide, or anagrelide.
 36. The combination as definedin claim 17 wherein the other therapeutic agent is an anti-Alzheimer'sagent or anti-dementia agent, which is tacrine HCl (Cognex®), donepezil(Aricept®), a γ-secretase inhibtor, a β-secretase inhibitor and/orantihypertensive agent; an antiosteoporosis agent, which is parathyroidhormone, a bisphosphonate, alendronate, a Ca receptor agonist or aprogestin receptor agonist; a hormone replacement therapeutic agent,which is a selective estrogen receptor modulator (SERM); a tyrosinekinase inhibitor; a selective androgen receptor modulator; anantiarrhythmic agent, which is a β-blocker, or a calcium channelblocker, or an α-adrenergic blocker; coenzyme Q sub. 10; an agent thatupregulates type III endothelial cell nitric acid syntase; achondroprotective compound which is polysulfated glycosaminoglycan(PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA),pentosan polysulfate (PPS), doxycycline or minocycline; a cyclooxygenase(COX)-2 inhibitor, which is Celebrex® (Searle) or Vioxx® (Merck) or aglycoprotein IIa/IIIb receptor antagonist; a 5-HT reuptake inhibitor; agrowth hormone secretagogue; an anti-atherosclerosis agent; ananti-infective agent, or an immunosuppressant for use intransplantation, or an antineoplastic agent.
 37. A method for treatinghypercholesterolemia, dyslipidemia, hyperlipidemia,hyperlipoproteinemia, LDL Pattern B, LDL Pattern A, hypertriglyceridemiaor atherosclerosis, or Alzheimer's disease or osteoporosis, whichcomprises administering to a mammalian species in need of treatment atherapeutically effective amount of a compound as defined in claim 1.38. A method of inhibiting cholesterol biosynthesis or lowering bloodserum cholesterol levels and/or modulating blood serum cholesterollevels, lowering LDL cholesterol and/or increasing HDL cholesterol, ortreating dyslipidemia, mixed dyslipidemia, LDL Pattern B, LDL Pattern A,hyperlipidemia, hypercholesterolemia, hypo α-lipoproteinemia,hyperlipoproteinemia or hypertriglyceridemia, and other aberrations ofapolipoprotein B metabolism, or reducing levels of Lp(a), or treating orpreventing other cholesterol-related diseases, or treating or preventingor reversing progression of atherosclerosis, or preventing or treatingAlzheimer's disease, or preventing or treating osteoporosis and/orosteopenia, or reducing inflammatory markers, reducing C-reactiveprotein, or preventing or treating low grade vascular inflammation, orpreventing or treating stroke, or preventing or treating dementia, orpreventing and treating coronary heart disease, and primary andsecondary prevention of myocardial infarction, or preventing or treatingstable and unstable angina, or primary prevention of coronary events, orsecondary prevention of cardiovascular events, or preventing or treatingperipheral vascular disease, preventing or treating peripheral arterialdisease, or preventing or treating acute vascular syndromes, orpreventing or reducing the risk of undergoing myocardialrevascularization procedures, or preventing or treating microvasculardiseases such as nephropathy, neuropathy, retinopathy and nephroticsyndrome, or preventing or treating hypertension in a patient in need ofsuch treatment, which comprises administering to a mammalian species inneed of treatment a therapeutically effective amount of a compound inaccordance with claim
 16. 39. A method for preventing or treatingdiabetes, especially Type 2 diabetes, and related diseases, insulinresistance, hyperglycemia, hyperinsulinemia, elevated blood levels offatty acids or glycerol, obesity, LDL Pattern B, LDL Pattern A, SyndromeX, diabetic complications, dysmetabolic syndrome, and related diseases,and sexual dysfunction, which comprises administering to a mammalianspecies in need of treatment a therapeutically effective amount of acompound as defined in claim
 1. 40. A method for preventing and treatingmalignant lesions, premalignant lesions, gastrointestinal malignancies,liposarcomas and epithelial tumors, cancer-induced asthenia (fatigue),irritable bowel syndrome, Crohn's disease, gastric ulceritis, andgallstones, and HIV infection, drug-induced lipodystrophy, andproliferative diseases, which comprises administering to a mammalianspecies in need of treatment a therapeutically effective amount of acompound as defined in claim
 1. 41. A method for improving coagulationhomeostasis, reducing PAI-1 activity, reducing fibrinogen, and/orreducing platelet aggregation, and/or improving endothelial function,which comprises administering to a mammalian species in need oftreatment a therapeutically effective amount of a compound as defined inclaim
 1. 42. A method for treating cholesterol related diseases,diabetes and related diseases, cardiovascular diseases, cerebrovasculardiseases, which comprises administering to a mammalian species in needof treatment a therapeutically effective amount of a combination of acompound as defined in claim 1 and a hypolipidemic agent, and/or lipidmodulating agent and/or antidiabetic agent and/or cardiovascular agent,cerebrovascular agent, and/or other type of therapeutic agent, whichcomprises administering to a mammalian species in need of treatment atherapeutically efective amount of such combinations.
 43. A compoundhaving the structure

wherein X is O, S or NR₇ where R₇ is H, alkyl, aryl, alkanoyl, aroyl oralkoxycarbonyl; R₁ and R₂ are the same or different and areindependently selected from alkyl, arylalkyl, cycloalkyl, alkenyl,cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl; R₉ and R₁₀ are thesame or different and are independently selected from H or alkyl, or R₉and R₁₀ may be taken together with the carbon or carbons to which theyare attached to form a 3 to 7 membered carbocyclic ring;


44. The compound as defined in claim 43 having the following structures: